Background Most dialysis patients require phosphate binders to control hyperphosphatemia. Ferric citrate has been tested in phase 2 trials as a phosphate binder. This trial was designed as a ...dose-response and efficacy trial. Study Design Prospective, phase 3, multicenter, open-label, randomized clinical trial. Setting & Participants 151 participants with hyperphosphatemia on maintenance hemodialysis therapy. Intervention Fixed dose of ferric citrate taken orally as a phosphate binder for up to 28 days (1, 6, or 8 g/d in 51, 52, and 48 participants, respectively). Outcomes Primary outcome is dose-response of ferric citrate on serum phosphorus level; secondary outcomes are safety and tolerability. Measurements Serum chemistry tests including phosphorus, safety data. Results 151 participants received at least one dose of ferric citrate. Mean baseline phosphorus levels were 7.3 ± 1.7 (SD) mg/dL in the 1-g/d group, 7.6 ± 1.7 mg/dL in the 6-g/d group, and 7.5 ± 1.6 mg/dL in the 8-g/d group. Phosphorus levels decreased in a dose-dependent manner (mean change at end of treatment, −0.1 ± 1.3 mg/dL in the 1-g/d group, −1.9 ± 1.7 mg/dL in the 6-g/d group, and −2.1 ± 2.0 mg/dL in the 8-g/d group). The mean difference in reduction in phosphorus levels between the 6- and 1-g/d groups was 1.3 mg/dL (95% CI, 0.69 to 1.9; P < 0.001), between the 8- and 1-g/d groups was 1.5 mg/dL (95% CI, 0.86 to 2.1; P < 0.001), and between the 8- and 6-g/d groups was 0.21 mg/dL (95% CI, −0.39 to 0.81; P = 0.5). The most common adverse event was stool discoloration. Limitations Sample size and duration confirm efficacy, but limit our ability to confirm safety. Conclusions Ferric citrate is efficacious as a phosphate binder in a dose-dependent manner. A phase 3 trial is ongoing to confirm safety and efficacy.
Background Secondary hyperparathyroidism is observed in patients with early chronic kidney disease (CKD). This study investigated the safety and efficacy of cinacalcet for secondary ...hyperparathyroidism in participants with CKD not receiving dialysis. Study Design Double-blind, randomized, 32-week, phase 3 study. Setting & Participants 404 participants with stage 3 or 4 CKD from 73 centers in 9 countries. Interventions Cinacalcet:placebo (3:1 ratio). Outcomes & Measurements Proportion of participants with a mean decrease of 30% or greater in intact parathyroid hormone (iPTH) level, proportion with iPTH level of 70 or less or 110 or less pg/mL (stage 3 and 4 CKD, respectively), and mean percentage of iPTH change from baseline, all during the efficacy-assessment phase. Results A greater proportion of cinacalcet than placebo participants achieved a 30% or greater decrease in iPTH level (74% versus 28%; P < 0.001), corresponding to a 43.1% decrease in iPTH level from baseline (cinacalcet) compared with a 1.1% increase (placebo). At week 32, serum calcium levels were 8.9 ± 0.8 mg/dL (−8.9%; cinacalcet) and 9.9 ± 0.6 mg/dL (+0.8%; placebo), phosphorus levels were 4.5 ± 1.0 mg/dL (+21.4%) and 4.0 ± 0.7 mg/dL (+6.8%), and calcium-phosphorus product values were 40.1 ± 8.3 mg2 /dL2 (+18.9%) and 38.9 ± 6.9 mg2 /dL2 (+17.1%), respectively. During the study course, 62% (cinacalcet) and 1% (placebo) of participants experienced 2 consecutive serum calcium concentrations less than 8.4 mg/dL. They generally were asymptomatic and without significant clinical consequences. Treatment generally was well tolerated, and most adverse events were mild to moderate in severity. Limitations The study was not designed to assess the effects of cinacalcet on vascular calcification, bone histomorphometric parameters, or other clinical outcomes. It is not known whether the observed differences in changes in iPTH levels are clinically more important than observed differences in changes in serum calcium or phosphorus levels or dosages of vitamin D sterols and phosphate binders. Conclusions These data show that cinacalcet treatment in patients with CKD not receiving dialysis can decrease plasma iPTH levels, but with frequent (albeit generally asymptomatic) serum calcium levels less than 8.4 mg/dL and increases in serum phosphorus levels.
Summary Background The ICON7 trial previously reported improved progression-free survival in women with ovarian cancer with the addition of bevacizumab to standard chemotherapy, with the greatest ...effect in patients at high risk of disease progression. We report the final overall survival results of the trial. Methods ICON7 was an international, phase 3, open-label, randomised trial undertaken at 263 centres in 11 countries across Europe, Canada, Australia and New Zealand. Eligible adult women with newly diagnosed ovarian cancer that was either high-risk early-stage disease (International Federation of Gynecology and Obstetrics FIGO stage I–IIa, grade 3 or clear cell histology) or more advanced disease (FIGO stage IIb–IV), with an Eastern Cooperative Oncology Group performance status of 0–2, were enrolled and randomly assigned in a 1:1 ratio to standard chemotherapy (six 3-weekly cycles of intravenous carboplatin AUC 5 or 6 and paclitaxel 175 mg/m2 of body surface area) or the same chemotherapy regimen plus bevacizumab 7·5 mg per kg bodyweight intravenously every 3 weeks, given concurrently and continued with up to 12 further 3-weekly cycles of maintenance therapy. Randomisation was done by a minimisation algorithm stratified by FIGO stage, residual disease, interval between surgery and chemotherapy, and Gynecologic Cancer InterGroup group. The primary endpoint was progression-free survival; the study was also powered to detect a difference in overall survival. Analysis was by intention to treat. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN91273375. Findings Between Dec 18, 2006, and Feb 16, 2009, 1528 women were enrolled and randomly assigned to receive chemotherapy (n=764) or chemotherapy plus bevacizumab (n=764). Median follow-up at the end of the trial on March 31, 2013, was 48·9 months (IQR 26·6–56·2), at which point 714 patients had died (352 in the chemotherapy group and 362 in the bevacizumab group). Our results showed evidence of non-proportional hazards, so we used the difference in restricted mean survival time as the primary estimate of effect. No overall survival benefit of bevacizumab was recorded (restricted mean survival time 44·6 months 95% CI 43·2–45·9 in the standard chemotherapy group vs 45·5 months 44·2–46·7 in the bevacizumab group; log-rank p=0·85). In an exploratory analysis of a predefined subgroup of 502 patients with poor prognosis disease, 332 (66%) died (174 in the standard chemotherapy group and 158 in the bevacizumab group), and a significant difference in overall survival was noted between women who received bevacizumab plus chemotherapy and those who received chemotherapy alone (restricted mean survival time 34·5 months 95% CI 32·0–37·0 with standard chemotherapy vs 39·3 months 37·0–41·7 with bevacizumab; log-rank p=0·03). However, in non-high-risk patients, the restricted mean survival time did not differ significantly between the two treatment groups (49·7 months 95% CI 48·3–51·1) in the standard chemotherapy group vs 48·4 months 47·0–49·9 in the bevacizumab group; p=0·20). An updated analysis of progression-free survival showed no difference between treatment groups. During extended follow-up, one further treatment-related grade 3 event (gastrointestinal fistula in a bevacizumab-treated patient), three grade 2 treatment-related events (cardiac failure, sarcoidosis, and foot fracture, all in bevacizumab-treated patients), and one grade 1 treatment-related event (vaginal haemorrhage, in a patient treated with standard chemotherapy) were reported. Interpretation Bevacizumab, added to platinum-based chemotherapy, did not increase overall survival in the study population as a whole. However, an overall survival benefit was recorded in poor-prognosis patients, which is concordant with the progression-free survival results from ICON7 and GOG-218, and provides further evidence towards the optimum use of bevacizumab in the treatment of ovarian cancer. Funding The National Institute for Health Research through the UK National Cancer Research Network, the Medical Research Council, and Roche.
Background Atopic dermatitis (AD) is a chronic inflammatory skin disease associated with increased susceptibility to recurrent skin infections. Objective We sought to determine why a subset of ...patients with AD have an increased risk of disseminated viral skin infections. Methods Human subjects with AD with a history of eczema herpeticum (EH) and various control groups were enrolled. Vaccinia virus (VV) expression was measured by means of PCR and immunofluorescent staining in skin biopsy specimens from each study group after incubation with VV. Transgenic mice with a constitutively active signal transducer and activator of transcription 6 gene (STAT6) were characterized for response to VV skin inoculation. Genotyping for 10 STAT6 single nucleotide polymorphisms (SNPs) was performed in a white patient sample (n = 444). Results VV gene and protein expression were significantly increased in the skin of patients with EH compared with other subject groups after incubation with VV in vitro . Antibody neutralization of IL-4 and IL-13 resulted in lower VV replication in patients with a history of EH. Mice that expressed a constitutively active STAT6 gene compared with wild-type mice had increased mortality and satellite lesion formation after VV skin inoculation. Significant associations were observed between STAT6 SNPs and EH (rs3024975, rs841718, rs167769, and rs703817) and IFN-γ production. The strongest association was observed for a 2-SNP haplotype (patients with AD with a history of EH vs patients with AD without a history of EH, 24.9% vs 9.2%; P = 5.17 × 10−6 ). Conclusion The STAT6 gene increases viral replication in the skin of patients with AD with a history of EH. Further genetic association studies and functional investigations are warranted.
OBJECTIVES:
Traumatic brain injury is associated with coagulopathy that increases mortality risk. Viscoelastic hemostatic assays such as thromboelastography (Haemonetics SA, Signy, Switzerland) ...provide rapid coagulopathy assessment and may be particularly useful for goal-directed treatment of traumatic brain injury patients. We conducted a systematic review to assess thromboelastography in the evaluation and management of coagulopathy in traumatic brain injury patients.
DATA SOURCES:
MEDLINE, PubMed Central, Embase, and CENTRAL.
STUDY SELECTION:
Clinical studies of adult patients with traumatic brain injury (isolated or polytrauma) who were assessed by either standard thromboelastography or thromboelastography with platelet mapping plus either conventional coagulation assays or platelet function assays from January 1999 to June 2021.
DATA EXTRACTION:
Demographics, injury mechanism and severity, diagnostic, laboratory data, therapies, and outcome data were extracted for analysis and comparison.
DATA SYNTHESIS:
Database search revealed 1,169 sources; eight additional articles were identified by the authors. After review, 31 publications were used for qualitative analysis, and of these, 16 were used for quantitative analysis. Qualitative and quantitative analysis found unique patterns of thromboelastography and thromboelastography with platelet mapping parameters in traumatic brain injury patients. Patterns were distinct compared with healthy controls, nontraumatic brain injury trauma patients, and traumatic brain injury subpopulations including those with severe traumatic brain injury or penetrating traumatic brain injury. Abnormal thromboelastography K-time and adenosine diphosphate % inhibition on thromboelastography with platelet mapping are associated with decreased survival after traumatic brain injury. Subgroup meta-analysis of severe traumatic brain injury patients from two randomized controlled trials demonstrated improved survival when using a viscoelastic hemostatic assay-guided resuscitation strategy (odds ratio, 0.39; 95% CI, 0.17–0.91;
p
= 0.030).
CONCLUSIONS:
Thromboelastography and thromboelastography with platelet mapping characterize coagulopathy patterns in traumatic brain injury patients. Abnormal thromboelastography profiles are associated with poor outcomes. Conversely, treatment protocols designed to normalize abnormal parameters may be associated with improved traumatic brain injury patient outcomes. Current quality of evidence in this population is low; so future efforts should evaluate viscoelastic hemostatic assay-guided hemostatic resuscitation in larger numbers of traumatic brain injury patients with specific focus on those with traumatic brain injury-associated coagulopathy.
Background This study investigated the factors influencing influenza vaccination rates among health care personnel (HCP) and explored HCP's attitudes toward a policy of mandatory vaccination. Methods ...In September 2012, a 33-item Web-based questionnaire was administered to 3,054 HCP employed at a tertiary care hospital in metropolitan Detroit. Results There was a significant increase in the rate of influenza vaccination, from 80% in the 2010-2011 influenza season (before the mandated influenza vaccine) to 93% in 2011-2012 (after the mandate) ( P < .0001). Logistic regression showed that HCP with a history of previous influenza vaccination were 7 times more likely than their peers without this history to receive the vaccine in 2011-2012. A pro-mandate attitude toward influenza vaccination was a significant predictor of receiving the vaccine after adjusting for demographics, history of previous vaccination, awareness of the hospital's mandatory vaccination policy, and patient contact while providing care ( P = .01). Conclusions The increased rate of influenza vaccination among HCP was driven by both an awareness of the mandatory policy and a pro-mandate attitude toward vaccination. The findings of this study call for better education of HCP on the influenza vaccine along with enforcement of a mandatory vaccination policy.
Background and Aims In patients who have undergone ERCP with biliary stenting for postsurgical bile leaks, the optimal method (ERCP or gastroscopy) and timing of stent removal is controversial. We ...developed a clinical prediction rule to identify cases in which a repeat ERCP is unnecessary. Methods Population-based study of all patients who underwent ERCP for management of surgically induced bile leaks between 2000 and 2012. Multivariate and binary recursive partitioning analyses were performed to generate a rule predicting the absence of biliary pathology on repeat endoscopic evaluation. Results A total of 259 patients were included. On multivariate analysis, postsurgical normal alkaline phosphatase (ALP; OR, 2.26; 95% CI, 1.03-4.99), time from surgery to first ERCP < 8 days (OR, 2.47; 95% CI, 1.15-5.31), and minor leak with no other pathology on initial ERCP (OR, 6.74; 95% CI, 1.75-25.89) were independently associated with the absence of persistent bile leak and other pathology on repeat ERCP. The derived rule included laparoscopic cholecystectomy, normal postsurgical ALP, minor leak with no other pathology on initial ERCP, and an interval from initial to repeat ERCP between 4 and 8 weeks. When all 4 criteria were met, the rule had a sensitivity of 94% (95% CI, 83%-99%) and a negative predictive value of 93% (95% CI, 81%-99%). Optimism-adjusted sensitivity and negative predictive value were 88% (95% CI, 76%-96%) and 86% (95% CI, 73%-96%), respectively. Conclusions This clinical decision rule identifies patients who can have their biliary stents removed via gastroscopy, which may improve patient safety and healthcare utilization.
Studies comparing carpal tunnel release with ultrasound guidance (CTR-US) to mini-open CTR (mOCTR) are limited. This randomized trial compared the efficacy and safety of these techniques.
In this ...multicenter randomized trial, patients were randomized (2:1) to unilateral CTR-US or mOCTR. Outcomes included Boston Carpal Tunnel Questionnaire Symptom Severity Scale (BCTQ-SSS) and Functional Status Scale (BCTQ-FSS), numeric pain scale (0-10), EuroQoL-5 Dimension 5-Level (EQ-5D-5L), scar outcomes, and complications over 1 year.
Patients received CTR-US (n = 94) via wrist incision (mean 6 mm) or mOCTR (n = 28) via palmar incision (mean 22 mm). Comparing CTR-US with mOCTR, the mean changes in BCTQ-SSS (-1.8 versus -1.8;
= 0.96), BCTQ-FSS (-1.0 versus -1.0;
= 0.75), numeric pain scale (-3.9 versus -3.8;
= 0.74), and EQ-5D-5L (0.13 versus 0.12;
= 0.79) over 1 year were comparable between groups. Freedom from scar sensitivity or pain favored CTR-US (95% versus 74%;
= 0.005). Complications occurred in 2.1% versus 3.6% of patients (
= 0.55), all within 3 weeks postprocedure. There was one revision surgery in the CTR-US group, and no revisions for persistent or recurrent symptoms in either group.
CTR-US and mOCTR demonstrated similar improvement in carpal tunnel syndrome symptoms and quality of life with comparable low complication rates over 1 year of follow-up. CTR-US was performed with a smaller incision and associated with less scar discomfort.
To evaluate the safety of stereotactic body radiation therapy (SBRT) for prostate cancer in men with inflammatory bowel disease (IBD).
We queried a consortium database for patients with IBD receiving ...SBRT for prostate cancer between 2006 and 2012. Identified patients were matched with patients without a history of IBD in a 3:1 fashion based on dose, fractionation, use of androgen deprivation therapy, and age distribution. Logistic regression was used to evaluate the association between having IBD and experiencing acute and late gastrointestinal (GI) and genitourinary (GU) toxicities as scored on the Common Terminology Criteria for Adverse Events scale. Time to late toxicity was evaluated using proportional hazard Cox models. Our study was limited by absence of data on prostate size, baseline International Prostate Symptom Score, and rectal dose-volume histogram parameters.
Thirty-nine patients with flare-free IBD at time of treatment (median follow-up 83.9 months) and 117 matched controls (median follow-up 88.7 months) were identified. A diagnosis of IBD was associated with increased odds of developing any late grade GI toxicity (odds ratio OR 6.11, P <.001) and GU toxicity (odds ratio 6.14, P < .001), but not odds of developing late grade ≥2 GI (P = .08) or GU toxicity (P = .069). Acute GI and GU toxicity, both overall and for grade ≥2 toxicities, were more frequent in men with IBD (P < .05). Time to late GI and GU toxicity of any grade was significantly shorter in patients with IBD (P < .001). Time to late grade ≥2 GU, but not grade ≥2 GI toxicity, was also shorter in patients with IBD (P = .044 for GU and P = .144 for GI).
Patients with IBD who received SBRT for PCa had a higher likelihood of developing acute GI and GU toxicity, in addition to experiencing lower grade late toxicities that occurred earlier. However, patients with IBD did not have a higher likelihood for late grade ≥2 GI or GU toxicity after SBRT compared with the control cohort. Interpretation of this data are limited by the small sample size. Thus, men with IBD in remission should be properly counseled about these risks when considering SBRT.
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