Dosimetry of human exposure to furan and 2-methylfuran by monitoring urinary biomarkers.

Furan and 2-methylfuran (2-MF) can form during food processing and accumulate in foods at various concentrations depending on processing technology and beverage/meal preparation methods applied prior to consumption. Here, we report a controlled dosimetry study with 20 volunteers (10 male, 10 female) to monitor dietary furan/2-MF exposure. The volunteers followed an eleven-day furan/2-MF-restricted diet in which they consumed freshly prepared coffee brew containing known amounts of furan and 2-MF on two separate occasions (250 mL and 500 mL on days 4 and 8, respectively). Urine was collected over the whole study period and analyzed for key metabolites derived from the primary oxidative furan metabolite cis-2-butene-1,4-dial (BDA) (i.e., Lys-BDA, AcLys-BDA and cyclic GSH-BDA) and the primary 2-MF metabolite acetylacrolein (AcA, 4-oxo-pent-2-enal) (i.e., Lys-AcA and AcLys-AcA). A previously established stable isotope dilution analysis (SIDA) method was utilized. Excretion kinetics revealed two peaks (at 0-2 and 24-36 h) for AcLys-BDA, Lys-BDA, AcLysAcA and LysAcA, whereas GSH-BDA showed a single peak. Notably, women on average excreted the metabolite GSH-BDA slightly faster than men, indicating gender differences. Overall, the study provided further insights into the spectrum of possible biomarkers of furan and 2-methyfuran metabolites occurring in the urine of volunteers after coffee consumption.

Adaptive irrigation management by Balinese farmers reduces greenhouse gas emissions and increases rice yields.

The potential for changes in water management regimes to reduce greenhouse gases (GHG) in rice paddies has recently become a major topic of research in Asia, with implications for top-down versus bottom-up management strategies. Flooded rice paddies are a major source of anthropogenic GHG emissions and are responsible for approximately 11% of global anthropogenic methane (CH4) emissions. However, rice is also the most important food crop for people in low- and lower-middle-income countries. While CH4 emissions can be reduced by lessening the time the plants are submerged, this can trigger increased emissions of nitrous oxide (N2O), a more potent GHG. Mitigation options for CH4 and N2O are different, and minimizing one gas may increase the emission of the other. Accurate measurement of these gas emissions in rice paddies is difficult, and the results are controversial. We analysed these trade-offs using continuous high-precision measurements in a closed chamber in 2018-2020. Based on the results, we tested a bottom-up adaptive irrigation regime that improves nitrogen uptake by rice plants while reducing combined GHG emissions and nitrogen runoff from paddies to reefs in agricultural drainages. In 2023, we undertook a follow-up study in which farmers obtained higher rice yields with adaptive intermittent irrigation compared to uniformly flooded fields. These results use the polycentric, self-governing capacity of Balinese subaks for continuous adaptation. This article is part of the theme issue 'Climate change adaptation needs a science of culture'.

Role of the bHLH transcription factor TCF21 in development and tumorigenesis.

Transcription factors control, coordinate, and separate the functions of distinct network modules spatially and temporally. In this review, we focus on the transcription factor 21 (TCF21) network, a highly conserved basic-helix-loop-helix (bHLH) protein that functions to integrate signals and modulate gene expression. We summarize the molecular and biological properties of TCF21 control with an emphasis on molecular and functional TCF21 interactions. We suggest that these interactions serve to modulate the development of different organs at the transcriptional level to maintain growth homeostasis and to influence cell fate. Importantly, TCF21 expression is epigenetically inactivated in different types of human cancers. The epigenetic modification or activation and/or loss of TCF21 expression results in an imbalance in TCF21 signaling, which may lead to tumor initiation and, most likely, to progression and tumor metastasis. This review focuses on research on the roles of TCF21 in development and tumorigenesis systematically considering the physiological and pathological function of TCF21. In addition, we focus on the main molecular bases of its different roles whose importance should be clarified in future research. For this review, PubMed databases and keywords such as TCF21, POD-1, capsulin, tumors, carcinomas, tumorigenesis, development, and mechanism of action were utilized. Articles were selected within a historical context as were a number of citations from journals with relevant impact.

Role of the bHLH transcription factor TCF21 in development and tumorigenesis

Transcription factors control, coordinate, and separate the functions of distinct network modules spatially and temporally. In this review, we focus on the transcription factor 21 (TCF21) network, a highly conserved basic-helix-loop-helix (bHLH) protein that functions to integrate signals and modulate gene expression. We summarize the molecular and biological properties of TCF21 control with an emphasis on molecular and functional TCF21 interactions. We suggest that these interactions serve to modulate the development of different organs at the transcriptional level to maintain growth homeostasis and to influence cell fate. Importantly, TCF21 expression is epigenetically inactivated in different types of human cancers. The epigenetic modification or activation and/or loss of TCF21 expression results in an imbalance in TCF21 signaling, which may lead to tumor initiation and, most likely, to progression and tumor metastasis. This review focuses on research on the roles of TCF21 in development and tumorigenesis systematically considering the physiological and pathological function of TCF21. In addition, we focus on the main molecular bases of its different roles whose importance should be clarified in future research. For this review, PubMed databases and keywords such as TCF21, POD-1, capsulin, tumors, carcinomas, tumorigenesis, development, and mechanism of action were utilized. Articles were selected within a historical context as were a number of citations from journals with relevant impact.

User-testing an interactive option grid decision aid for prostate cancer screening: lessons to improve usability.

OBJECTIVE: To user-test a web-based, interactive Option Grid decision aid 'prostate-specific antigen (PSA) test: yes or no?' to determine its usability, acceptability and feasibility with men of high and low health literacy. DESIGN: A semi-structured interview study. SETTING: Interviews were conducted at a senior centre, academic hospital or college library in New Hampshire and Vermont. PARTICIPANTS: Individuals over 45 years of age with no history of prostate cancer who voluntarily contacted study authors after viewing local invitations were eligible for inclusion. Twenty interviews were conducted: 10 participants had not completed a college degree, of which eight had low health literacy, and 10 participants had high health literacy. INTERVENTION: An interactive, web-based Option Grid patient decision aid for considering whether or not to have a PSA test. RESULTS: Users with lower health literacy levels were able to understand the content in the tool but were not able to navigate the Option Grid independent of assistance. The tool was used independently by men with high health literacy. In terms of acceptability, the flow of questions and answers embedded in the tool did not seem intuitive to some users who preferred seeing more risk information related to age and family history. Users envisioned that the tool could be feasibly implemented in clinical workflows. CONCLUSION: Men in our sample with limited health literacy had difficulty navigating the Option Grid, thus suggesting that the tool was not appropriately designed to be usable by all audiences. The information provided in the tool is acceptable, but users preferred to view personalised risk information. Some participants could envision using this tool prior to an encounter in order to facilitate a better dialogue with their clinician. ETHICS APPROVAL: The study received ethical approval from the Dartmouth College Committee for the Protection of Human Subjects (STUDY00030116).

Persistence of low disease activity after tumour necrosis factor inhibitor (TNFi) discontinuation in patients with psoriatic arthritis.

OBJECTIVE: To determine the duration of clinical benefit among patients with psoriatic arthritis (PsA) discontinuing tumour necrosis factor inhibitor (TNFi) therapy while in low disease activity (LDA), and to identify patient characteristics associated with prolonged clinical benefit. METHODS: We performed an observational cohort study assessing patients with PsA from the Consortium of Rheumatology Researchers of North America (CORRONA) registry who had discontinued TNFi after achieving LDA, defined as clinical disease activity index (CDAI) score ≤10 and physician's global assessment (PGA) of skin psoriasis ≤20/100. Kaplan-Meier method was used to estimate the duration of clinical benefit. RESULTS: Of the 5945 patients with PsA in CORRONA, 302 patients had discontinued TNFi (n=325) while in LDA and had follow-up data available. At time of discontinuation, mean PsA duration was 9.8 years, mean CDAI was 3.9, and mean duration of TNFi use was 1.5 years; 52.6% of patients had discontinued their first TNFi. Median time to loss of benefit was 29.2 months. 179 (55.1%) patients had persistent benefit at their previous clinic visit. An increased risk of losing clinical benefit was seen among patients with higher disease activity at discontinuation (CDAI≥3.2 vs <3.2; HR 1.43 (p=0.32)) and among smokers (HR 1.78 (p=0.027)). CONCLUSIONS: Patients with PsA who achieve LDA may maintain clinical benefit after discontinuation of TNFi therapy.

[Intraoperative stress in orthopaedic spine surgery : Attending surgeon versus resident]. / Intraoperativer Stress bei Wirbelsäuleneingriffen : Operateur vs. Assistent.

INTRODUCTION: Requirements for orthopaedic spine surgeons include occupational skills, concentration, physical fitness and psychological stress resistance, depending on the attending surgeon's or the resident's position. MATERIAL AND METHODS: This study measured and evaluated stress-relevant cardiovascular parameters during 101 spinal surgical procedures of a 40-year old fellowship-trained spine surgeon with 12 years of practice. A training computer, personal scales and a thermometer were used to record the duration of surgery, heart rate, weight loss and calorie burning. RESULTS: The average maximum heart rate as an attending surgeon (124 bpm) was significantly higher than the resident's heart rate (99 bmp). A higher stress level resulted in an increasingly higher average maximum heart rate according to the duration of surgery. The mean loss of body fluids at an average room temperature of 20.4 C after surgery was 0.82 kg (0 to 2.3 kg). The mean loss of body weight was calculated as 1.12% of the attending surgeon versus 0.59% of the resident. DISCUSSION: Increasing complexity, longer duration and a higher potential of intraoperative complications arouse a strong response from the attending surgeon. The observed cardiovascular parameters are similar to those of a moderate to intense workout such as cycling. Long lasting surgeries result in a weight loss equivalent to a mild dehydration ranging from 2 to 5% of body fluids. Increasing dehydration will eventually worsen cognitive, visual and motor skills. Results of this study suggest early rehydration and utilization of mental relaxation techniques to minimize risks during prolonged, complex spine surgeries.

Derivation and internal validation of an expanded cardiovascular risk prediction score for rheumatoid arthritis: a Consortium of Rheumatology Researchers of North America Registry Study.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of mortality in rheumatoid arthritis (RA), but CV risk prediction scores derived from the general population do not accurately predict CV risk in RA patients. The goal of these analyses was to develop and internally validate an expanded CV risk prediction score for RA. METHODS: Study participants were patients with RA and no known CVD from the Consortium of Rheumatology Researchers of North America registry. Two-thirds of the cohort were used to derive the CV risk prediction score, and one-third for internal validation. Traditional CV risk factors were included in the base Cox regression model, and RA-related variables were assessed in an expanded model predicting confirmed CV events. Fit and utility of the expanded model were evaluated. RESULTS: The study cohort included 23,605 RA patients with 437 CV events over a median followup of 2.2 years. The RA variables found to be significant in the regression models and included in the expanded risk model were disease activity (Clinical Disease Activity Index >10 versus ≤10), disability (modified Health Assessment Questionnaire disability index >0.5 versus ≤0.5), daily prednisone use (any versus none), and disease duration (≥10 years versus <10 years). The expanded model had good fit (Hosmer-Lemeshow goodness of fit P = 0.94) and a lower Akaike's information criterion than the base model. In the internal validation cohort, the c-statistic for model discrimination was significantly improved from the base model to the expanded model (from 0.7261 to 0.7609; P = 0.0104). The net reclassification index of CV risk in models using a 4-category CV risk prediction tool was 40% (95% confidence interval 37-44%). CONCLUSION: This newly developed, expanded risk score for CV outcomes in RA performs well and improves the classification of CV risk in comparison to a risk prediction score in which only traditional risk factors were included.

Evaluation of an effective multifaceted implementation strategy for elective single-embryo transfer after in vitro fertilization.

STUDY QUESTION: What is the relationship between the rate of elective single-embryo transfer (eSET) and couples' exposure to different elements of a multifaceted implementation strategy? SUMMARY ANSWER: Additional elements in a multifaceted implementation strategy do not result in an increased eSET rate. WHAT IS KNOWN ALREADY: A multifaceted eSET implementation strategy with four different elements is effective in increasing the eSET rate by 11%. It is unclear whether every strategy element contributes equally to the strategy's effectiveness. STUDY DESIGN AND SIZE: An observational study was performed among 222 subfertile couples included in a previously performed randomized controlled trial. PARTICIPANTS, SETTINGS AND METHODS: Of the 222 subfertile couples included, 109 couples received the implementation strategy and 113 couples received standard IVF care. A multivariate regression analysis assessed the effectiveness of four different strategy elements on the decision about the number embryos to be transferred. Questionnaires evaluated the experiences of couples with the different elements. MAIN RESULTS AND ROLE OF CHANCE: Of the couples who received the implementation strategy, almost 50% (52/109) were exposed to all the four elements of the strategy. The remaining 57 couples who received two or three elements of the strategy could be divided into two further classes of exposure. Our analysis demonstrated that additional elements do not result in an increased eSET rate. In addition to the physician's advice, couples rated a decision aid and a counselling session as more important for their decision to transfer one or two embryos, compared with a phone call and a reimbursement offer (P < 0.001). LIMITATIONS AND REASONS FOR CAUTION: The differences in eSET rate between exposure groups failed to reach significance, probably because of the small numbers of couples in each exposure group. WIDER IMPLICATIONS OF THE FINDINGS: Adding more elements to an implementation strategy does not always result in an increased effectiveness, which is in concordance with recent literature. This in-depth evaluation of a multifaceted intervention strategy could therefore help to modify strategies, by making them more effective and less expensive.

Safety and efficacy of ocrelizumab in patients with rheumatoid arthritis and an inadequate response to at least one tumor necrosis factor inhibitor: results of a forty-eight­week randomized, double-blind, placebo-controlled, parallel-group phase III trial.

OBJECTIVE: To evaluate the safety and efficacy of ocrelizumab plus methotrexate (MTX) or leflunomide (LEF) in patients with active rheumatoid arthritis (RA) and an inadequate response to tumor necrosis factor α inhibitors. METHODS: This was a multicenter randomized, double-blind, placebo-controlled, parallel-group study that continued over 48 weeks. Patients receiving stable doses of MTX or LEF were randomized to receive 2 infusions of placebo (n = 277), ocrelizumab 200 mg (n = 278), or ocrelizumab 500 mg (n = 285) on days 1 and 15 as well as at weeks 24 and 26. Coprimary end points were the proportion of patients with response according to the American College of Rheumatology 20% improvement criteria (ACR20) at weeks 24 and 48. Secondary end points included the change from baseline in the modified Sharp/van der Heijde score (SHS) and the ACR50/70 responses. RESULTS: ACR20 responses were 22.0% in the placebo group, 42.2% in the ocrelizumab 200 mg group, and 47.9% in the ocrelizumab 500 mg group at 24 weeks and 19.5%, 48.7%, and 50.7%, respectively, at 48 weeks (P < 0.0001 versus placebo for each comparison at each time point). At 48 weeks, patients receiving both doses of ocrelizumab showed significantly improved ACR50 and ACR70 responses of ~3-fold versus placebo. Only those in the ocrelizumab 500 mg group showed statistically significant (P = 0.0017) inhibition of joint damage progression (mean change in the SHS) relative to placebo (61% inhibition) at 48 weeks. Overall adverse events and infections during the 48 weeks of study were comparable in all treatment groups. Serious infections were observed more frequently in patients taking ocrelizumab (5.1% and 4.3%) than in those taking placebo (2.5%). CONCLUSION: Patients in both of the ocrelizumab groups met the clinical primary efficacy end points. Inhibition of change in the SHS was statistically significant at 48 weeks for those in the ocrelizumab 500 mg group. The rate of serious infections in this trial was higher for both ocrelizumab doses as compared with placebo.

Greater remission rates in patients with early versus long-standing disease in biologic-naive rheumatoid arthritis patients treated with abatacept: a post hoc analysis of randomized clinical trial data.

OBJECTIVES: Current aim of rheumatoid arthritis (RA) treatment is to achieve remission in as many patients as possible. Rates of remission and clinical outcomes after treatment with abatacept in biologic-naive rheumatoid arthritis (RA) patients with early disease and an inadequate response to methotrexate (MTX) versus patients with ≥ 10 years of disease were assessed. METHODS: Data from two trials assessing the efficacy of abatacept in MTX inadequate responders were pooled for this exploratory post hoc analysis. Patients with disease duration of ≤ 2 years at baseline (early disease), originally assigned to an abatacept approximately 10 mg/kg treatment arm and entered into a long-term extension (LTE), were compared with patients with ≥ 10 years of disease (long-standing RA). Remission, DAS28-CRP, ACR 70 responses and the Routine Assessment of Patient Index Data 3 (RAPID3), improvement in physical function as measured by the Health Assessment Questionnaire Disability Index (HAQ-DI). RESULTS: Twenty-three percent of these patients (n=108) had early disease. A higher percentage of patients with early disease achieved DAS28-CRP remission versus patients with long-standing disease (35.2% vs. 19.4% at year 1, p<0.01; 46.0% vs. 30.9% at year 3, p<0.05). In addition, a higher percentage of the subgroup with early RA achieved ACR70 responses. More patients with early RA had a meaningful improvement in their HAQ-DI (75.2% vs. 60.4%; p<0.05) and RAPID3 scores at one year (mean changes from baseline of -9.6 vs. -8.1; p=0.009). CONCLUSIONS: These data provide additional support for the possible use of abatacept in biologic-naive patients who have had inadequate response to MTX, earlier in their disease course.

Is the fertility treatment itself a risk factor for early pregnancy loss?

This longitudinal multicentre cohort study aimed to identify the role of the conception mode in infertile couples with an early pregnancy loss (EPL). All couples referred to the fertility clinic for the first time in the period 2002-2006 because of infertility were followed up to their first clinical pregnancy (n=1809). EPL was the outcome of 286 (15.8%) pregnancies. EPL rates for the different conception modes were as follows: spontaneous 14.5% (125/864), ovulation induction 15.8% (42/266), intrauterine insemination 25.0% (5/20), intrauterine insemination combined with ovarian stimulation 18.2% (37/203), IVF 16.3% (31/190), intracytoplasmic sperm injection (ICSI) 14.9% (30/202) and frozen embryo transfer (FET) 26.2% (16/61). After adjusting for female age, male age, hospital, obstetric history, female smoking habit, male alcohol use, menstrual cycle type and infertility diagnosis, the EPL rate after FET was significantly increased (odds ratio 2.2, 95% CI 1.14-4.19) compared with spontaneous conception. Embryo quality was comparable in fresh and frozen embryos. Other fertility treatments showed no increased miscarriage rate. Therefore, it is concluded that even after adjustment for confounding factors conception through FET remained an independent risk factor for EPL. Other modes of conception were not related with EPL.

In vitro 17ß-oestradiol release as a marker for follicular survival in cryopreserved intact bovine ovaries.

Transplantation of cryopreserved intact ovaries from cancer patients is a technically challenging option for restoring fertility after sterilizing cancer therapy. In this paper we describe an assay based on 17ß-oestradiol (oestradiol) production, to monitor the functional damage sustained by the ovarian tissue during the freeze/thawing procedure. To this end, fresh bovine ovarian cortical biopsies were cultured in vitro for 7 days. As a control, the oestradiol release of biopsies that had sustained maximal cryodamage was analyzed. In addition the oestradiol release by cortical biopsies from two ME2SO perfused and cryopreserved intact ovaries was analyzed. Oestradiol production could be measured in culture supernatants, while oestradiol release of maximal cryo-damaged biopsies was at background levels. In vitro oestradiol release by cortical biopsies can be used as a functional marker for cryo-damage and indicates that our assay is suitable to optimize the cryopreservation procedure of intact ovaries.

Improved pain, physical functioning and health status in patients with rheumatoid arthritis treated with CP-690,550, an orally active Janus kinase (JAK) inhibitor: results from a randomised, double-blind, placebo-controlled trial.

OBJECTIVES: To determine the efficacy of CP-690,550 in improving pain, function and health status in patients with moderate to severe active rheumatoid arthritis (RA) and an inadequate response to methotrexate or a tumour necrosis factor alpha inhibitor. METHODS: Patients were randomised equally to placebo, CP-690,550 5, 15 or 30 mg twice daily for 6 weeks, with 6 weeks' follow-up. The patient's assessment of arthritis pain (pain), patient's assessment of disease activity, Health Assessment Questionnaire-Disability Index (HAQ-DI) and Short Form-36 (SF-36) were recorded. RESULTS: At week 6, significantly more patients in the CP-690,550 5, 15 and 30 mg twice-daily groups experienced a 50% improvement in pain compared with placebo (44%, 66%, 78% and 14%, respectively), clinically meaningful reductions in HAQ-DI (> or =0.3 units) (57%, 75%, 76% and 36%, respectively) and clinically meaningful improvements in SF-36 domains and physical and mental components. CONCLUSIONS: CP-690,550 was efficacious in improving the pain, function and health status of patients with RA, from week 1 to week 6.

Association of methotrexate and tumour necrosis factor antagonists with risk of infectious outcomes including opportunistic infections in the CORRONA registry.

OBJECTIVE: To examine the association of methotrexate (MTX) and tumour necrosis factor (TNF) antagonists with the risk of infectious outcomes including opportunistic infections in patients with rheumatoid arthritis (RA). METHODS: Patients with RA enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) registry prescribed MTX, TNF antagonists or other disease-modifying antirheumatic drugs (DMARDs) were included. The primary outcomes were incident overall and opportunistic infections. Incident rate ratios were calculated using generalised estimating equation Poisson regression models adjusted for demographics, comorbidities and RA disease activity measures. RESULTS: A total of 7971 patients with RA were followed. The adjusted rate of infections per 100 person-years was increased among users of MTX (30.9, 95% CI 29.2 to 32.7), TNF antagonists (40.1, 95% CI 37.0 to 43.4) and a combination of MTX and TNF antagonists (37.1, 95% CI 34.9 to 39.3) compared with users of other non-biological DMARDs (24.5, 95% CI 21.8 to 27.5). The adjusted incidence rate ratio (IRR) was increased in patients treated with MTX (IRR 1.30, 95% CI 1.12 to 1.50) and TNF antagonists (IRR 1.52, 95% CI 1.30 to 1.78) compared with those treated with other DMARDs. TNF antagonist use was associated with an increased risk of opportunistic infections (IRR 1.67, 95% CI 0.95 to 2.94). Prednisone use was associated with an increased risk of opportunistic infections (IRR 1.63, 95% CI 1.20 to 2.21) and an increased risk of overall infection at doses >10 mg daily (IRR 1.30, 95% CI 1.11 to 1.53). CONCLUSIONS: MTX, TNF antagonists and prednisone at doses >10 mg daily were associated with increased risks of overall infections. Low-dose prednisone and TNF antagonists (but not MTX) increased the risk of opportunistic infections.

Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide.

INTRODUCTION: Potential hepatotoxicity associated with disease-modifying antirheumatic drugs (DMARDs) requires laboratory monitoring. In patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA), the incidence of elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) enzymes associated with methotrexate (MTX), leflunomide (LEF) and MTX+LEF versus other DMARDs was examined. METHODS: Patients with RA and PsA enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) initiating DMARDs were identified. Abnormalities were identified when either was 1- or 2-fold times above the upper limits of normal (ULN). Odds ratios (OR) between MTX/LEF dose and elevated ALT/AST enzymes were estimated using generalised estimating equations. Interaction terms for use of MTX+LEF quantified the incremental risk of the combination compared with each individually. RESULTS: Elevated ALT/AST levels (>1x ULN) occurred in 22%, 17%, 31% and 14% of patients with RA receiving MTX, LEF, MTX+LEF or neither, respectively; elevations were 2.76-fold (95% CI 1.84 to 4.15) more likely in patients with PsA. Elevations >2x ULN occurred in 1-2% of patients on MTX or LEF monotherapy compared with 5% with the combination. After multivariable adjustment and compared with either monotherapy, the combination of MTX and LEF was associated with a greater risk according to MTX dose used as part of the combination: MTX 10-17.5 mg/week, OR 2.91 (95% CI 1.23 to 6.90); MTX > or =20 mg/week, OR 3.98 (95% CI 1.72 to 9.24). CONCLUSIONS: Abnormal ALT/AST levels developed in 14-35% of patients with RA or PsA initiating DMARD therapy. The risks were incrementally greater in those with PsA and in those receiving MTX (> or =10 mg/day) + LEF. These findings should help inform monitoring for potential hepatotoxicity in these patient populations.

The COX-2 inhibitor market withdrawals and prescribing patterns by rheumatologists in patients with gastrointestinal and cardiovascular risk.

OBJECTIVE: To examine effects of the COX-2 inhibitor market withdrawals on NSAID utilization among patients at increased risk of gastrointestinal (GI) and cardiovascular (CV) toxicities. METHODS: A prospective cohort study was conducted using patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) Registry. The study population included rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients prescribed NSAIDs by rheumatologists from 1/1/2003 to 12/31/2005. Three cohorts were defined based on calendar year. The primary outcome assessed whether or not an NSAID gastroprotective strategy was prescribed. Secondary outcomes included rates of COX-2 inhibitor utilization and gastroprotective co-therapy utilization, stratified by the presence of cardiac and GI risk factors. RESULTS: NSAID gastroprotection utilization decreased from 65.1% in 2003 to 47.7% (p<0.001) in 2005. COX-2 inhibitor use decreased from 55.1% to 29.2% (p<0.001), whereas nonselective NSAIDs (nsNSAIDs) use increased from 50.2% to 73.9% (p=<0.01). Among patients with two or more risk factors for NSAID related GI bleeding, gastroprotection decreased from 74.4% in 2003 to 60.9% (p<0.01). For patients with two or more CV risk factors from 2003 to 2005, COX-2 inhibitor utilization decreased significantly, whereas nsNSAID utilization increased significantly. CONCLUSIONS: The COX-2 inhibitor withdrawals resulted in a rapid decline in NSAID gastroprotection prescribed by participating U.S. rheumatologists despite the availability of other gastroprotective options. Channeling toward nsNSAID use was widespread, including among patients at increased CV risk. Longer term follow-up is required to determine the clinical significance of these changes in NSAID prescribing, particularly for NSAID-related GI and CV-related toxicities.

IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial.

OBJECTIVES: The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy. METHODS: 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed. RESULTS: ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups. CONCLUSION: Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile. TRIAL REGISTRATION NUMBER: NCT00106522.

Improvement in patient-reported outcomes in a rituximab trial in patients with severe rheumatoid arthritis refractory to anti-tumor necrosis factor therapy.

OBJECTIVE: To assess the effects of treatment with rituximab plus methotrexate on patient-reported outcomes in patients with active rheumatoid arthritis (RA) who experienced inadequate response to anti-tumor necrosis factor therapy. METHODS: Patients with active RA were randomly assigned to rituximab (1,000 mg on days 1 and 15) or placebo. The primary end point was the proportion of patients with an American College of Rheumatology 20% response at week 24. Additional goals were to assess treatment effects on pain, fatigue, functional disability, health-related quality of life, and disease activity by comparing mean changes between groups. The analysis was conducted in the intent-to-treat population. The proportion of patients who achieved the minimum clinically important difference on the Health Assessment Questionnaire (HAQ) disability index (DI), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and Short Form 36 (SF-36) was determined. RESULTS: Rituximab patients had statistically significantly greater pain relief. The FACIT-F showed significantly greater improvement in rituximab patients than placebo patients from weeks 12 through 24. Mean improvement from baseline in functional disability (measured by the HAQ DI) was significantly greater in rituximab patients from weeks 8 to 24. The mean +/- SD change from baseline for the SF-36 Physical Component Score was 6.64 +/- 8.74 for rituximab patients and 1.48 +/- 7.32 for placebo patients (P < 0.0001). The mean change from baseline for the SF-36 Mental Component Score was 5.32 +/- 12.41 for rituximab patients and 2.25 +/- 12.23 for placebo patients (P = 0.0269). CONCLUSION: Rituximab produced rapid, clinically meaningful, and statistically significant improvements in patient-reported pain, fatigue, functional disability, health-related quality of life, and disease activity. These effects were sustained throughout the study.

Cervical insemination versus intra-uterine insemination of donor sperm for subfertility.

BACKGROUND: Insemination with donor sperm is an option for couples for whom in vitro fertilisation (IVF) or intra-cytoplasmic sperm injection (ICSI) has been unsuccessful, couples with azoospermia and for single women or same sex couples. Insemination of sperm can be done via cervical (CI) or intra-uterine (IUI) routes. IUI has been considered potentially more effective than CI as the sperm bypasses the cervical mucus and is deposited closer to the fallopian tubes. The cost and risks of IUI may be higher because of the need for sperm preparation and the introduction of foreign material into the uterus. Donor sperm used for artificial insemination is mainly cryopreserved, due to concerns about HIV transmission. However, cycle fecundity is higher for fresh sperm. Insemination is often combined with ovulatory stimulation, with either clomiphene or gonadotrophin. There may be risks associated with these therapies, such as higher multiple pregnancy rates. OBJECTIVES: To determine whether pregnancy outcomes are improved using intra-uterine insemination in comparison to cervical insemination in women undergoing artificial insemination with donor sperm. SEARCH STRATEGY: The following databases were searched: the Cochrane Menstrual Disorders and Subfertility Group Specialised Register, CENTRAL (The Cochrane Library) , MEDLINE, EMBASE, CINAHL and the reference lists of articles retrieved. SELECTION CRITERIA: Randomised controlled trials comparing IUI with CI were included. Crossover studies were included if pre-crossover data was available. DATA COLLECTION AND ANALYSIS: Study quality assessment and data extraction were carried out independently by two review authors (DB, JM). Authors of studies that potentially met the inclusion criteria were contacted, where possible if additional information was needed. MAIN RESULTS: The search strategy found 232 articles. Fifteen studies potentially met the inclusion criteria. Four studies were included in this review. All the included studies used cryopreserved sperm in stimulated cycles. In two studies 134 women had gonadotrophin-stimulated cycles and in two studies 74 women had clomiphene-stimulated cycles. The evidence showed that IUI after 6 cycles significantly improved live birth rates (odds ratio (OR) 1.98, 95% confidence interval (CI) 1.02 to 3.86) and pregnancy rates (OR 3.37, 95% CI 1.90 to 5.96) in comparison to cervical insemination. There was no statistically significant evidence of an effect on multiple pregnancies (OR 2.19, 95% CI 0.79 to 6.07) or miscarriages (relative risk (RR) 3.92, 95% CI 0.85 to 17.96). AUTHORS' CONCLUSIONS: The findings of this systematic review support the use of IUI rather than CI in stimulated cycles using cryopreserved sperm for donor insemination.