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National Institutes of Health Stroke Scale (NIHSS), measured a few hours to days after stroke onset, is an attractive outcome measure for stroke research. NIHSS at the time of presentation (baseline NIHSS) strongly predicts the follow-up NIHSS. Because of the need to account for the baseline NIHSS in the analysis of follow-up NIHSS as an outcome measure, a common and intuitive approach is to define study outcome as the change in NIHSS from baseline to follow-up (ΔNIHSS). However, this approach has important limitations. Analyzing ΔNIHSS implies a very strong assumption about the relationship between baseline and follow-up NIHSS that is unlikely to be satisfied, drawing into question the validity of the resulting statistical analysis. This reduces the precision of the estimates of treatment effects and the power of clinical trials that use this approach to analysis. ANCOVA allows for the analysis of follow-up NIHSS as the dependent variable while adjusting for baseline NIHSS as a covariate in the model and addresses several challenges of using ΔNIHSS outcome using simple bivariate comparisons (eg, a t test, Wilcoxon rank-sum, linear regression without adjustment for baseline) for stroke research. In this article, we use clinical trial simulations to illustrate that variability in NIHSS outcome is less when follow-up NIHSS is adjusted for baseline compared to ΔNIHSS and how a reduction in this variability improves the power. We outline additional, important clinical and statistical arguments to support the superiority of ANCOVA using the final measurement of the NIHSS adjusted for baseline over, and caution against using, the simple bivariate comparison of absolute NIHSS change (ie, delta).

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited., Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19., Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020., Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108)., Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%)., Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively., Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions., Trial Registration: ClinicalTrials.gov Identifier: NCT02735707.

Introduction: As the population ages, there is interest in strategies to promote resiliency, especially for frail patients at risk of its complications. The physiological stress of surgery in high-risk individuals has been proposed both as an important cause of accelerated age-related decline in health and as a model testing the effectiveness of strategies to improve resiliency to age-related health decline. We describe a randomised, embedded, multifactorial, adaptative platform (REMAP) trial to investigate multiple perioperative interventions, the first of which is metformin and selected for its anti-inflammatory and anti-ageing properties beyond its traditional blood glucose control features., Methods and Analysis: Within a multihospital, single healthcare system, the Core Protocol for Strategies to Promote ResiliencY (SPRY) will be embedded within both the electronic health record (EHR) and the healthcare culture generating a continuously self-learning healthcare system. Embedding reduces the administrative burden of a traditional trial while accessing and rapidly analysing routine patient care EHR data. SPRY-Metformin is a placebo-controlled trial and is the first SPRY domain evaluating the effectiveness of three metformin dosages across three preoperative durations within a heterogeneous set of major surgical procedures. The primary outcome is 90-day hospital-free days. Bayesian posterior probabilities guide interim decision-making with predefined rules to determine stopping for futility or superior dosing selection. Using response adaptative randomisation, a maximum of 2500 patients allows 77%-92% power, detecting >15% primary outcome improvement. Secondary outcomes include mortality, readmission and postoperative complications. A subset of patients will be selected for substudies evaluating the microbiome, cognition, postoperative delirium and strength., Ethics and Dissemination: The Core Protocol of SPRY REMAP and associated SPRY-Metformin Domain-Specific Appendix have been ethically approved by the Institutional Review Board and are publicly registered. Results will be publicly available to healthcare providers, patients and trial participants following achieving predetermined platform conclusions., Trial Registration Number: NCT03861767., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There is broad interest in improved methods to generate robust evidence regarding best practice, especially in settings where patient conditions are heterogenous and require multiple concomitant therapies. Here, we present the rationale and design of a large, international trial that combines features of adaptive platform trials with pragmatic point-of-care trials to determine best treatment strategies for patients admitted to an intensive care unit with severe community-acquired pneumonia. The trial uses a novel design, entitled "a randomized embedded multifactorial adaptive platform." The design has five key features: 1 ) randomization, allowing robust causal inference; 2 ) embedding of study procedures into routine care processes, facilitating enrollment, trial efficiency, and generalizability; 3 ) a multifactorial statistical model comparing multiple interventions across multiple patient subgroups; 4 ) response-adaptive randomization with preferential assignment to those interventions that appear most favorable; and 5 ) a platform structured to permit continuous, potentially perpetual enrollment beyond the evaluation of the initial treatments. The trial randomizes patients to multiple interventions within four treatment domains: antibiotics, antiviral therapy for influenza, host immunomodulation with extended macrolide therapy, and alternative corticosteroid regimens, representing 240 treatment regimens. The trial generates estimates of superiority, inferiority, and equivalence between regimens on the primary outcome of 90-day mortality, stratified by presence or absence of concomitant shock and proven or suspected influenza infection. The trial will also compare ventilatory and oxygenation strategies, and has capacity to address additional questions rapidly during pandemic respiratory infections. As of January 2020, REMAP-CAP (Randomized Embedded Multifactorial Adaptive Platform for Community-acquired Pneumonia) was approved and enrolling patients in 52 intensive care units in 13 countries on 3 continents. In February, it transitioned into pandemic mode with several design adaptations for coronavirus disease 2019. Lessons learned from the design and conduct of this trial should aid in dissemination of similar platform initiatives in other disease areas.Clinical trial registered with www.clinicaltrials.gov (NCT02735707).

Background: Fluticasone furoate (FF)/vilanterol (VI) is a once-daily inhaled corticosteroid (ICS)/long-acting beta 2 agonist (LABA) combination. FF/VI, 92/22mcg and 184/22mcg, are approved in Europe as maintenance therapy in persistent asthma. We report data from mixed treatment comparisons (MTC) of once-daily FF/VI against established twice-daily ICS/LABA combination therapies on clinical efficacy outcomes., Methods: Data from 31 parallel-group randomised controlled trials (RCTs) of ICS/LABA, of ≥8 weeks' duration in patients aged ≥12 years with asthma, identified by systematic review, were analysed using covariate-adjusted Bayesian hierarchical models for four efficacy outcomes (primary analysis). Lung function, assessed by change from baseline morning peak expiratory flow (PEF) ( n  = 18 studies) and forced expiratory volume in 1 s (FEV 1 ) ( n  = 28), was the outcome of primary interest. Secondary objectives were assessment of relative efficacy in terms of exacerbation rates ( n  = 6) and health status ( n  = 7). Overall, 24 different treatment arms were included in the MTC; we report findings comparing FF/VI (92/22mcg and 184/22mcg) with fluticasone propionate/salmeterol (FP/SAL) (250/50mcg and 500/50mcg) and budesonide/formoterol (BUD/FORM) (320/9mcg and 640/18mcg)., Results: For PEF (margin = 12 l/min), FF/VI 92/22mcg demonstrated ≥94 % probability and FF/VI 184/22mcg >99 % probability of non-inferiority to corresponding doses of both FP/SAL and BUD/FORM. For FEV 1 (margin = 100 ml), FF/VI demonstrated ≥98 % (92/22mcg) and >99 % (184/22mcg) probability of non-inferiority to both FP/SAL and BUD/FORM. Findings for exacerbations were inconclusive due to lack of data: FF/VI 92/22mcg demonstrated 74 % and 82 % probability of non-inferiority (margin = 10 %) to FP/SAL 250/50mcg and BUD/FORM 320/9mcg, respectively. For Asthma Quality of Life Questionnaire (AQLQ) score, FF/VI 92/22mcg demonstrated >99 % and 90 % probability of non-inferiority (margin = 0.25) to FP/SAL 250/50mcg and BUD/FORM 320/9mcg. Data were unavailable to assess non-inferiority of FF/VI 184/22mcg on exacerbations or AQLQ., Conclusions: Both strengths of once-daily FF/VI in asthma were comparable with corresponding doses of twice-daily FP/SAL and BUD/FORM in terms of lung function in this MTC analysis. FF/VI 92/22mcg was comparable with FP/SAL and BUD/FORM on AQLQ, but exacerbation results were inconclusive. Model limitations include disconnected treatment networks and variability across studies. Our data support previous RCT findings suggesting that the efficacy of once-daily FF/VI in improving lung function and health status in asthma is comparable with twice-daily ICS/LABAs.

Background: Fluticasone furoate (FF)/vilanterol (VI) 100/25 mcg is a once-daily inhaled corticosteroid (ICS)/long-acting beta2 agonist (LABA) treatment approved in the United States, Canada and Europe for the long-term maintenance therapy of COPD. We report data from mixed treatment comparisons (MTC) of once-daily FF/VI against established twice-daily ICS/LABA combination therapies on clinical efficacy outcomes., Methods: Data from 33 parallel-group randomised controlled trials (RCTs) of ICS/LABAs, of ≥8 weeks' duration in patients ≥12 years of age with COPD, identified by systematic review, were analysed using covariate-adjusted Bayesian hierarchical models for three efficacy outcomes. Lung function, assessed by change from baseline in forced expiratory volume in one second (FEV1), was the outcome of primary interest (n = 28 studies). Secondary objectives were assessment of annual rate of moderate/severe exacerbations (n = 15) and patient-reported health status, measured by change from baseline in St George's Respiratory Questionnaire (SGRQ) Total score (n = 20). Overall, 25 different treatments were included in the MTC; we report findings, including probabilities of non-inferiority, for comparisons of once-daily FF/VI 100/25 mcg with twice-daily fluticasone propionate (FP)/salmeterol (SAL) 500/50 mcg and budesonide (BUD)/formoterol (FORM) 400/12 mcg., Results: For FEV1, FF/VI 100/25 mcg demonstrated >99% probability of non-inferiority to FP/SAL 500/50 mcg and BUD/FORM 400/12 mcg using a 50 mL margin. For annual rate of moderate/severe exacerbations, FF/VI 100/25 mcg demonstrated 73% and 77% probability of non-inferiority to FP/SAL 500/50 mcg and BUD/FORM 400/12 mcg, respectively, using a 10% rate ratio margin. For SGRQ Total score, the corresponding probabilities of non-inferiority were 99% and 98%, respectively, on a 2-unit margin. Significant covariate effects were identified: increased age was associated with deterioration in FEV1 and reduced exacerbation frequency; shorter study duration was associated with reduced exacerbation frequency., Conclusions: FF/VI 100/25 mcg was comparable with corresponding doses of FP/SAL and BUD/FORM on lung function and health status outcomes. Non-inferiority on moderate/severe exacerbation rate was not demonstrated to the same degree of confidence, though observed rates were similar. Model limitations include a weak treatment network for the exacerbation analysis and variability across the included studies. Our data support previous RCT findings suggesting that the efficacy of FF/VI 100/25 mcg on lung function and health status in COPD is comparable with twice-daily ICS/LABAs.

Background: Melanoma that metastasizes to distant sites is associated with a grave prognosis. The objectives of the study were (1) to identify predictive factors for the development of brain metastases from the time of diagnosis of stage III/IV disease, (2) to identify predictive factors for the development of central nervous system (CNS) metastases from the time of diagnosis of primary melanoma, and (3) to assess whether the incidence of brain metastasis is more frequent in patients who had no tumor response to systemic therapy for stage III/IV disease compared with those who had partial or complete response., Patients and Methods: We collected and retrospectively analyzed information of 740 patients with advanced metastatic melanoma treated at MD Anderson Cancer Center over 15 years. Three hundred and twenty-nine patients had CNS metastases. The characteristics of these patients in terms of median age, sex, primary site, Breslow thickness, stage at first visit, baseline serum parameters, and response to systemic therapy were compared with those of patients who did not develop CNS metastasis. Cox proportional hazards models were used to analyze the cause-specific hazard function for CNS metastasis and deaths without CNS metastasis., Results: We identified that M-stage [stage M1b vs. stage III or M1a, hazard ratio (HR)=2.64; stage M1c vs. stage III or M1a, HR=2.13, P<0.0001] and lactic acid dehydrogenase (LDH) (elevated vs. normal LDH, HR=1.51, P<0.001) at diagnosis of unresectable stage III/IV disease can independently predict the risk of developing CNS metastasis from the time of diagnosis of stage III/IV disease. Older age (HR=1.01, P=0.076), chemoresistance (stable disease+progressive disease vs. complete response+partial response HR=2.91, P<0.0001), low level of albumin (vs. normal HR=2.87, P<0.0001), elevated LDH (vs. normal HR=1.55, P=0.0004), and M-stage (M1c disease vs. stage III or M1a HR=1.89, P<0.0001) can independently predict shorter time to death without CNS metastasis from the diagnosis of stage III/IV disease. The location (head and neck vs. limbs HR=1.56, P=0.028; trunk and abdomen vs. limbs HR=1.45, P=0.029; unknown site vs. limbs HR=8.43, P=0.036) and pathology [Clark level (CL)=3 and/or BR2 to 4 mm vs. CL≤2 and/or BR<2 mm HR=1.60, P=0.037; CL>3 and/or BR> 4 mm vs. CL≤2 and/or BR<2 mm HR=2.03, P=0.001) of the primary melanoma can independently predict CNS metastasis-free interval from the time of diagnosis of primaries. Age (HR=1.012, P=0.034) and pathology of the primary melanoma (CL>3 and/or BR>4 mm vs. CL≤2 and/or BR<2 mm HR=1.54, P=0.024) can independently predict time to death without CNS metastasis from primaries., Conclusion: We identified the predictive factors associated with the development of CNS metastasis in patients with unresectable metastatic melanoma.

Hematopoietic stem-cell transplantation (HSCT) is associated with high rates of gonadal failure, which is distressing for younger patients desiring to start a family. The perceived importance and optimal timing of discussing fertility- and menopause-related information with women undergoing aggressive treatment such as HSCT is not well defined. Questionnaires were sent to 532 patients who underwent HSCT between January 1987 and September 2004 at the ages of 16 to 50 years. The questionnaire assessed demographic data, the need for fertility- and menopause-related information at various times during treatment, and standardized measures of anxiety, quality of life, and menopausal symptoms. The return rate was 40.2%, with 196 patients participating. Of these, 38% reported that they had discussed fertility-related issues with health-care providers since their diagnosis; 54% had discussed menopause-related issues. At the time of diagnosis, participants considered receiving information on fertility and menopause as being of equal importance. However, after HSCT, information about menopause was considered more important than information on fertility (P < or = .0001). Being <40 years, being childless, desiring to bear children in the future, and having a high score on the State-Trait Anxiety Inventory (STAI) correlated with higher ratings of importance for both fertility- and menopause-related information. Our results suggested that healthcare providers should provide information on fertility and menopause repeatedly throughout the treatment period, and that menopause-related information should be reemphasized after HSCT. Such counseling is crucial for patients who are young and childless.

Purpose: The Pascal dynamic contour tonometer (DCT) was designed to measure IOP independently of corneal properties. This study aimed at 1) assessing the intra- and interindividual variability of DCT IOP measurements, the differences between DCT and applanation tonometry IOP measurements (APL), and their correlations with central corneal thickness (CCT); 2) analyzing the variability of the ocular pulse amplitude (OPA) and its correlations with age, blood pressure (BP), cardiac beat pulse (CP), diagnosis of glaucoma, IOP, and severity of glaucomatous visual field (VF) defects., Methods: Twenty-five normal subjects (25 eyes), 14 patients with ocular hypertension (27 eyes), and 54 glaucomatous patients (104 eyes) were included in this prospective study. In the first 12 normal subjects, three consecutive IOP measurements were taken by three different observers using DCT, directly followed by three measurements with APL by the same observer. In the following 13 subjects, the reverse sequence was followed. In the other group, the IOP measurements (three DCT and three APLs) were taken by the same observer. Only DCT measurements with quality levels 1-3 were considered for analysis., Results: In the normal group, DCT IOP measurement variability varied between 4.4%-7.3% (intraobserver variation coefficient) and 8% (interobserver variation coefficient). DCT IOP measurement was not influenced by the sequence of measurements or the observer. DCT overestimated IOP by a mean of 2.2 mmHg compared with APL (p<0.001). The 95% limits of agreement for each subject tested with both tonometers ranged from -0.5 mmHg to +6.3 mmHg. IOP APL and DCT measurements were strongly correlated. Both DCT and APL were not correlated with CCT. OPA ranged from 1.2 mmHg to 6.6 mmHg (mean, 3.1+/-1.2 mmHg) and was comparable between the three observers. Intraobserver OPA variability ranged from 7.6% to 9.5%. The interobserver OPA variability coefficient was 8.8%. OPA was only correlated with systolic BP (p<0.05). In glaucomatous patients, the correlation between DCT and APL IOP measurements was highly significant (r=0.860, p<0.001). DCT overestimated IOP by a mean 2 mmHg compared with APL (p<0.001). IOP differences between both tonometers were not influenced by the sequence of measurements. Unlike APL, DCT was not or only slightly influenced by CCT (p=0.07 for DCT; p=0.001 for APL). The mean difference between IOP DCT and APL was larger in thin corneas (<520 microm): 2.8+/-3.1 mmHg versus 0.8+/-2.3 mmHg in thick corneas (580 microm) (p=0.001). OPA was not correlated with age. It was positively correlated with IOP (p<0.001), systolic BP (p=0.047), and MD (mean deviation) (p=0.018). It was negatively correlated with diastolic BP (p=0.003), cardiac frequency (p<0.001), severity of glaucomatous VF defects (p=0.002), and PSD (pattern standard deviation) (p=0.008). It was significantly higher in the OHT subgroup and significantly lower in the NTG subgroup (p<0.05). In both groups, the IOP difference between DCT and APL was not correlated with age (p>0.05)., Conclusions: IOP measurements with the Pascal(R) DCT and APL correlated well and were reproducible. DCT IOP measurement variability was slightly higher than APL with relatively wide 95% limits of agreement. Considering the entire study population, DCT overestimated IOP by a mean 2.0 mmHg compared with APL. DCT was independent of CCT, especially in thin corneas. The DCT does not appear to be clinically advantageous over the Goldmann tonometer in the IOP measurement in thick corneas. Therefore an IOP follow-up by APL tonometry and pachymetry appeared to be mandatory for the interpretation of the true IOP. Interindividual OPA variations were high, as was measurement variability. OPA was correlated with BP, cardiac frequency, IOP, diagnosis of glaucoma, and severity of glaucomatous VF defects. These must be considered in the clinical interpretation of this parameter.

Purpose: The Icare dynamic tonometer (impact or Rebound tonometry) is a new tonometer based on making a moving object collide with an eye and on monitoring the motion parameters of this object following contact. The purpose of this study was to assess intra- and interobserver variability of IOP measurements with the Icare and their correlations with Goldmann applanation tonometry (GAT) and central corneal thickness (CCT)., Material and Methods: A prospective study including three groups of patients: group 1 (50 normal subjects), group 2 (50 patients with OHT or POAG and GAT IOP>22 mmHg), and group 3 (38 glaucomatous patients with GAT IOP< or =22 mmHg). In group 1, three consecutive IOP measurements were taken by three distinct observers with Icare followed by three GAT measurements by the same clinician. In group 2, the same procedure was followed from patients 1 to 25 and the reverse sequence from patients 25 to 50 after a 10-min break. In group 3, only one clinician took three GAT measurements followed by three Icare measurements after a 10-min break to exclude a tonographic effect in eyes with statistically normal-range IOPs., Results: : In group 1, intraobserver variability was about 6% for each observer (NS). There was no learning curve effect. The interobserver variation coefficient was 6.4%. Icare overestimated IOP compared to GAT (mean difference, 1.5-2.2 mmHg) (p<0.001). Icare IOP was 23.4 mmHg for observer 1 when GAT was 22 mmHg (95% individual CI, 18-28.9 mmHg). In group 2, intraobserver variation coefficients of the IOP ranged from 5% to 5.4% (NS). Icare overestimated IOP by mean 0.84 mmHg compared with GAT. In group 3, mean IOP was not different between Icare and GAT. Icare IOP of 20.7 mmHg corresponded to a value of 22 mmHg using GAT. In this group, correlations between CCT and IOP measurements were higher for Icare than for GAT (p=0.062)., Conclusion: Icare measures IOP in an unanesthetized sitting patient in a very brief time. Patient's minimal cooperation is needed. As long as the device is correctly positioned, the learning curve is short. Icare gives reproducible IOP measurements. Intra- and interobserver variability of IOP measurements are close to those of GAT. Icare overestimates IOP measurements an average 1.5 mmHg compared with GAT. Whatever the IOP level, Icare IOP measurements are well correlated with GAT. To a greater extent than for GAT, the reliability of IOP measurements is influenced by CCT. This tonometer can be used as a screening device for ocular hypertension as long as CCT measurements can be taken.

Purpose: Nodal disease in the setting of metastatic renal cell carcinoma is associated with poor prognosis. However, to our knowledge the biology of nodal metastases in the absence of metastatic disease is unknown. We reviewed our experience with treating this subset of patients with aggressive surgical resection., Materials and Methods: A total of 2,643 patients underwent nephrectomy at our institution between 1993 and 2003, including 40 with positive lymph nodes but no systemic metastases. All 40 patients underwent nephrectomy with extended retroperitoneal lymphadenectomy and they are the subjects of this study. Pathological characteristics and clinical outcomes were assessed., Results: Median patient age was 58 years and 62% of the patients were male. Median tumor size was 11 cm. Local stage was T1 in 3% of cases, T2 in 17%, T3a in 30%, T3b in 47% and T4 in 3%. Perinephric fat invasion was present in 77% of patients and positive margins were identified in 17%. Nodal status was N1 in 30% of patients and N2 in 70%, including 10 with masses of matted nodes. Histology was conventional in 63% of cases and papillary in 17%. The remaining 20% of patients had sarcomatoid dedifferentiation. Excluding the 10 patients with matted nodes the median number of nodes harvested per patient was 7 with a median of 2 that were positive. Extranodal extension was present in 70% of cases, while in 70% disease recurred at a median of 4.9 months. Median actuarial disease specific survival was 20.3 months. At a median followup of 17.7 months 30% of patients had no evidence of disease, 8% had disease and 62% had died. On multivariate analysis more than 1 positive node was predictive of decreased recurrence-free survival (HR 2.83, 95% CI 1.06 to 7.61, p = 0.039) and overall survival (HR 9.33, 95% CI 1.85 to 47.09, p = 0.007)., Conclusions: Nodal metastasis with renal cell carcinoma is an independent predictor of prognosis in patients with M0 disease. Even in the absence of distant metastatic disease patients with positive nodes should be targeted for aggressive surgical resection, followed by clinical trials of adjuvant therapy to improve the outcome.

Purpose: To compare the incidence and the severity of short-and medium-term complications following "modern" trabeculectomy (mTRAB) with non-penetrating deep sclerectomy (NPDS)., Materials and Methods: Comparative retrospective nonrandomized study including 65 eyes (55 patients) (mean age: 68.6 years) with medically uncontrolled glaucoma. mTRAB was performed in 43 eyes, NPDS in 22 eyes. mTRAB was performed according to a slightly modified P.T. Khaw protocol. NPDS procedures were done according to Kozlov's and Mermoud's technique with SKGEL implant in 18/22 eyes. Intraoperative antimetabolites (AMETAB) were given in 25 eyes (58%) in the mTRAB and 17 (77%) in the NPDS (p>0.05)., Results: Mean follow-up was longer in NPDS (10.7+/-5.5 months) than in mTRAB (8.5+/-3.4 months) (p<0.05). Preoperatively, the two groups were comparable in respect of age, type of glaucoma, mean IOP, severity of VF defects and bleb failure risk factors (p>0.05). Peroperatively, mTRAB were uneventful in 86% vs 90% of NPDS. 1st month postop complications occurred in 60.4% in mTRAB and 77.2% in NPDS (P>0.05). Most of them were minor and transient in both surgeries. Postop early anterior chamber inflammation was mild to moderate in all cases. The incidence of wound leaks (21% in the mTRAB group and 18% in the NPDS group) and hyperfiltration related complications (14% and 13.6% respectively in the mTRAB and NPDS group) were comparable between the two procedures (p > 0.05). Intraoperative antimetabolite application was not associated with an increased rate of postoperative hyperfiltration related complications. Scarring of filtration blebs had concerned a lower percentage of mTRAB eyes (19%) than the NPDS (36%). The number for 5-FU injections was less - although not significantly - in the mTRAB than in the other group (18.6% in mTRAB versus 41% in NPDS (p=0.05). Late complications were not observed in the mTRAB group. Iris prolapse associated with increased IOP occurred in 3 of the 22 NPDS procedures (13.6%). Final mean visual acuity was unchanged compared with preop value and was similar between the 2 groups (p>0.05). Diffuse, mildly vascularized filtration blebs were observed in 84% in mTRAB and 64% in DS (p>0.05). Mean IOP significantly decreased from 24.8+/-8.3 mm Hg to 13.4+/-4,3 mm Hg in mTRAB and from 25.1+/-6.5 mm Hg to 14.7+/-4.6 mm Hg in DS (p> 0.05). It was not different between the 2 groups with and without AMETAB augmentation. 70% of the mTRAB achieved a final IOP < or = 15 mmHg vs 41% in NPDS (p<0.05). The mean number of postop medications was 0.49 in mTRAB and 0.96 in NPDS (p<0.05). Complete (target IOP reached without meds) and qualified (target IOP reached with and without meds) final success rates were 60% and 88% in mTRAB and 36.4% and 68.2% in NPDS (p>0.05)., Conclusions: Whether surgery was augmented with intraoperative antimetabolite or not, mTRAB revealed as a priority to be associated with comparable and even less complications than deep sclerectomy. Owing to the limitations of our study and until further confirmation, our results have suggested that mTRAB was associated with a slightly more important IOP reduction as well as higher success rates than NPDS.

Purpose: To assess the long-term safety and effectiveness of non penetrating deep sclerectomy (DS) and to compare the incidence and the severity of postoperative complications and the IOP results according to surgical adjuvants (implant device, antimetabolite or both) were used or not., Material-Methods: Retrospective non randomised study including 171 eyes (136 patients), mean age: 63.9 years) with medically uncontrolled open-angle glaucoma and without previous filtering surgery. 81 eyes (48.2%) had severe glaucomatous damage. All procedures were performed according to the Kozlov's and Memoud's technique. Except for 8 eyes, they were associated with the placement of an implant device (SKGEL or T-FUX) and/or intra-operative application of low dose antimetabolite (5-FU in 58 eyes and mitomycine C in 53 eyes)., Results: Mean follow-up was 39.6 +/- 18.3 months. According to surgery, DS were categorized in 4 groups: Group 1: DS with Healon GV (n=8)(4.7%); Group 2: DS with antimetabolite application (n=26) (15.2%); Group 3: DS with placement of an implant (n=53) (31%). Group 4: intraoperative antimetabolite +implant device (n=84 eyes) (49.1%). Peroperative microperforations without iris hernia occurred in 35 eyes (21%). 1st month postoperative complications were observed in 90 eyes (52.6%) with mild to moderate hyperfiltration in 27 eyes, excessive scarring of filtration bleb in 38 eyes, and iris incarceration in 10 eyes. 5-FU injections were given in 58 eyes (34%). YAG gonioperforation was needed in 107/171 eyes (63%) and was complicated by iris incarceration in 9 eyes. Early and late spontaneous iris incarceration was observed in 10 eyes. A second filtering procedure was needed in 10 eyes.

The production of chimeric mice is a complex process, requiring the careful coordination of tissue culture cell growth, production of a large number (30-75) of competent blastocysts and the availability of appropriately timed pseudo pregnant female mice. Failure at any of these steps can impinge upon the rapid production of chimeras. One potential improvement for the efficient generation of chimeric mice would be the utilization of cryopreserved embryos suitable for injection. C57Bl/6 morulae were frozen using a standard 2-step protocol with ethylene glycol as the cryopreservation agent. We determined that cryopreserved morulae could thaw, culture to blastocyst stage in KSOM media and survive injection at rates equivalent to control embryos. Cryopreserved morulae were also equivalent to controls at all later stages in the process of production of chimeric mice, including birth rate, percentage chimerism of resulting animals and ability to produce germline progeny. Hence, cryopreservation of morulae for blastocyst injection is a suitable option to enhance the efficiency of chimeric mouse generation.

Ivermectin is the first oral treatment available for scabies. It is however not licensed for use in Belgium. In this article, we review its mechanism of action, its preferential indications among which crusted scabies and institutional outbreaks, its contra-indications and its advantages in comparison with topical treatments.

Isothiocyanates (ITCs) are nonnutrient compounds in cruciferous vegetables with anticarcinogenic properties. One proposed mechanism for their protective action is through down-regulation of cytochrome P-450 biotransformation enzyme levels and induction of phase II detoxifying enzymes. Because ITCs also serve as a substrate for GSTs, we evaluated dietary intake of ITCs and GSTM1 and GSTT1 genotype information in a lung cancer case-control study. There were 503 newly diagnosed lung cancer cases (264 men and 239 women) identified from The University of Texas M. D. Anderson Cancer Center and 465 controls (252 men and 213 women) recruited from enrollees in a local managed care organization. Subjects had an in-person interview including a semiquantitative food frequency questionnaire, and blood samples were obtained for genotyping. Cases reported significantly lower ITC intake per day compared with controls (P = 0.009). There was no main effect associated with the GSTM1 null genotype [odds ratio (OR) = 1.09]. However, there was a statistically significant OR of 1.41 associated with the GSTT1 null genotype. On stratified analysis, low ITC intake and the GSTM1 null genotype were associated with increased lung cancer risk in current smokers, with an OR of 2.22 [confidence interval (CI) = 1.20-4.10). For current smokers with the GSTT1 null genotype, the OR with low ITC intake was 3.19 (CI = 1.54-6.62). The comparable OR in the presence of both null genotypes was 5.45 (CI = 1.72-17.22). These effects were not demonstrable for former smokers by GSTM1 genotype, although the risk for low ITC intake and GSTT1 null genotype was 1.79 (CI = 0.95-3.37). Thus, current smokers who are homozygous null for the GST null genotype and who consume less carcinogenic blocking compounds are at higher lung cancer risk. Some of the inconsistencies reported in the role of GST genotypes in lung cancer risk could be due to unexpected confounding from dietary factors.

Recent research suggests that variant alleles (A1 and B1) of the DRD2 gene play a role in determining smoking status. However, no studies have evaluated these variant alleles in African-Americans and Mexican-Americans. The primary objective of this study, therefore, was to test the hypothesis that ever smokers in these ethnic groups are more likely than never smokers to have the DRD2 alleles associated with tobacco use (A1 and B1). Furthermore, because of a predicted higher prevalence of smokers in a family because of the patterns of inheritance of the genotypes associated with tobacco use, we also anticipated that individuals with these at-risk DRD2 alleles would be more likely to have a family history of smoking-related cancers. Because other inherited genetic variants may interact with smoking on cancer risk, we also hypothesized that this association might differ between cancer patients and control subjects. PCR was used to perform genotyping on peripheral WBC DNA from 140 lung cancer patients (43 Mexican-Americans and 97 African-Americans) and 222 age-, sex-, and ethnicity-matched controls (111 Mexican-Americans and 111 African-Americans). A personal family history was obtained from each participant. There were no statistically significant differences in the distribution of the DRD2 genotypes between cases and controls, although the frequency of the B1 genotype significantly differed by ethnicity (P = 0.002 for controls and P = 0.001 for cases). The DRD2 genotypes and smoking status showed a correlation among Mexican-American controls, although not among African-American controls. The cigarette pack-years in control subjects for the two ethnic groups combined were 30.8, 21.9, and 18.6 for the A1A1, A1A2, and A2A2 genotypes and 36.5, 20.8, and 18.5 for the B1B1, B1B2, and B2B2 genotypes, respectively. Similar trends were found for the number of cigarettes smoked per day among control subjects. From the standpoint of polymorphisms, however, there was a borderline significantly increased (3.6 times greater) frequency of smoking-related cancers among the first-degree relatives of case subjects with an A1 allele than among those without an A1 allele. There was also an elevated (1.8 times greater) frequency of smoking-related cancer among first-degree relatives of case subjects with a B1 allele compared with patients without a B1 allele, but this finding was not statistically significant. This phenomenon was not observed among control subjects. We noted a trend toward interaction of DRD2 A1 genotypes and case status for increased risk of smoking-related cancer among first-degree relatives. These findings suggest that the variant DRD2 genotypes are associated with a greater likelihood to smoke and a greater smoking intensity, as well as with a familial aggregation of smoking-related cancers. However, a large study is needed to confirm this finding.

Objectives: A supplemental test was evaluated for hepatitis C virus (HCV)., Methods: One hundred forty-six sera that were inconclusive or discrepant in two screening tests for HCV infection were evaluated using a supplemental test, MATRIX-HCV2 (Abbott Laboratories, Chicago, IL, USA). Results of the supplemental test were compared to the detection of HCV RNA by a nested polymerase chain reaction after a step of reverse transcription (RT-PCR)., Results: Thirty-nine RNA-containing sera (positive with RT-PCR) of 40 (97%) reacted with at least one antigen in the supplemental test. Reactivity with one to three antigens also was observed with 77 PCR-negative sera (66%). Twenty-nine sera were found negative with both techniques., Conclusions: Despite clear results and good sensitivity, the MATRIX-HCV2 assay was poorly predictive of viremia in patients with indeterminate results in initial screening assays.

The authors describe a case of iatrogenic Cushing's syndrome in which an emergency orbital decompression was performed. This procedure was necessary because major ocular hypertension and severe bilateral exophthalmos had caused a decrease in visual function and recurrent painful episodes of eyeball luxation.