Special Considerations for Advanced Heart Failure Surgeries: Durable Left Ventricular Devices and Heart Transplantation.

Heart transplantation and durable left ventricular assist devices (LVADs) represent two definitive therapies for end-stage heart failure in the modern era. Despite technological advances, both treatment modalities continue to experience unique risks that impact surgical and perioperative decision-making. Here, we review special populations and factors that impact risk in LVAD and heart transplant surgery and examine critical decisions in the management of these patients. As both heart transplantation and the use of durable LVADs as destination therapy continue to increase, these considerations will be of increasing relevance in managing advanced heart failure and improving outcomes.

Effect of Roflumilast Cream (ARQ-151) on Itch and Itch-Related Sleep Loss in Adults with Chronic Plaque Psoriasis: Patient-Reported Itch Outcomes of a Phase 2b Trial.

BACKGROUND: Itch is the most bothersome symptom reported by patients with psoriasis. Safe and effective treatments for psoriasis that also address itch are needed. OBJECTIVES: To report effects of roflumilast cream on itch-related outcomes from a Phase 2b trial. METHODS: Adults with chronic plaque psoriasis were randomized to roflumilast 0.3%, roflumilast 0.15%, or vehicle once-daily for 12 weeks. Psoriasis severity was assessed via the Investigator Global Assessment (IGA; a 5-point scale assessing plaque thickening, scaling, and erythema ranging from 0 [clear] to 4 [severe]) and ≥ 2 on a modified Psoriasis Area and Severity Index (PASI-HD, which combines severity of lesions and area affected, ranging from 0 [no disease] to 72 [maximal disease], with the actual percentage of the anatomical area involved in those patients with < 10% of anatomical area involved [e.g., 0.1 for 1% to 0.9 for 9%]). Itch was evaluated via Worst Itch Numeric Rating Scale (WI-NRS), Psoriasis Symptom Diary (PSD) Items 1 (severity of itch) and 2 (bother of itch), and itch-related sleep loss NRS scores. Post hoc correlation analyses between WI-NRS and PASI, WI-NRS and itch-related sleep loss, and WI-NRS and DLQI were also performed. RESULTS: Roflumilast-treated patients had significantly greater improvements than vehicle-treated patients in WI-NRS and PSD Items 1 and 2 beginning at Week 2 and in itch-related sleep loss Weeks 6 through 12. Among patients with baseline WI-NRS ≥ 6, significantly more patients achieved ≥ 4-point improvement with roflumilast than with vehicle as early as Week 2. Itch severity had low correlation with PASI while WI-NRS and IGA were not always aligned. LIMITATIONS: The first assessment was at 2 weeks, limiting the ability to assess early onset of itch response. CONCLUSION: Roflumilast cream improved itch and itch-related sleep loss associated with chronic plaque psoriasis. GOV IDENTIFIER: NCT03638258.

Effect of Roflumilast Cream vs Vehicle Cream on Chronic Plaque Psoriasis: The DERMIS-1 and DERMIS-2 Randomized Clinical Trials.

Importance: Once-daily roflumilast cream, 0.3%, a potent phosphodiesterase 4 inhibitor, demonstrated efficacy and was well tolerated in a phase 2b trial of patients with psoriasis. Objective: To evaluate the efficacy of roflumilast cream, 0.3%, applied once daily for 8 weeks in 2 trials of patients with plaque psoriasis. Design, Setting, and Participants: Two phase 3, randomized, double-blind, controlled, multicenter trials (DERMIS-1 [trial 1; n = 439] and DERMIS-2 [trial 2; n = 442]) were conducted at 40 centers (trial 1) and 39 centers (trial 2) in the US and Canada between December 9, 2019, and November 16, 2020, and between December 9, 2019, and November 23, 2020, respectively. Patients aged 2 years or older with plaque psoriasis involving 2% to 20% of body surface area were enrolled. The dates of final follow-up were November 20, 2020, and November 23, 2020, for trial 1 and trial 2, respectively. Interventions: Patients were randomized 2:1 to receive roflumilast cream, 0.3% (trial 1: n = 286; trial 2: n = 290), or vehicle cream (trial 1: n = 153; trial 2: n = 152) once daily for 8 weeks. Main Outcomes and Measures: The primary efficacy end point was Investigator Global Assessment (IGA) success (clear or almost clear status plus ≥2-grade improvement from baseline [score range, 0-4]) at week 8, analyzed using a Cochran-Mantel-Haenszel test stratified by site, baseline IGA score, and intertriginous involvement. There were 9 secondary outcomes, including intertriginous IGA success, 75% reduction in Psoriasis Area and Severity Index (PASI) score, and Worst Itch Numeric Rating Scale score of 4 or higher at baseline achieving 4-point reduction (WI-NRS success) at week 8 (scale: 0 [no itch] to 10 [worst imaginable itch]; minimum clinically important difference, 4 points). Results: Among 881 participants (mean age, 47.5 years; 320 [36.3%] female), mean IGA scores in trial 1 were 2.9 [SD, 0.52] for roflumilast and 2.9 [SD, 0.45] for vehicle and in trial 2 were 2.9 [SD, 0.48] for roflumilast and 2.9 [SD, 0.47]) for vehicle. Statistically significantly greater percentages of roflumilast-treated patients than vehicle-treated patients had IGA success at week 8 (trial 1: 42.4% vs 6.1%; difference, 39.6% [95% CI, 32.3%-46.9%]; trial 2: 37.5% vs 6.9%; difference, 28.9% [95% CI, 20.8%-36.9%]; P < .001 for both). Of 9 secondary end points, statistically significant differences favoring roflumilast vs vehicle were observed for 8 in trial 1 and 9 in trial 2, including intertriginous IGA success (71.2% vs 13.8%; difference, 66.5% [95% CI, 47.1%-85.8%] and 68.1% vs 18.5%; difference, 51.6% [95% CI, 29.3%-73.8%]; P < .001 for both), 75% reduction in PASI score (41.6% vs 7.6%; difference, 36.1% [95% CI, 28.5%-43.8%] and 39.0% vs 5.3%; difference, 32.4% [95% CI, 24.9%-39.8%]; P < .001 for both), WI-NRS success (67.5% vs 26.8%; difference, 42.6% [95% CI, 31.3%-53.8%] and 69.4% vs 35.6%; difference, 30.2% [95% CI, 18.2%-42.2%]; P < .001 for both). The incidence of treatment-emergent adverse events was 25.2% with roflumilast vs 23.5% with vehicle in trial 1 and 25.9% with roflumilast vs 18.4% with vehicle in trial 2. The incidence of serious adverse events was 0.7% with roflumilast vs 0.7% with vehicle in trial 1 and 0% with roflumilast vs 0.7% with vehicle in trial 2. Conclusions and Relevance: Among patients with chronic plaque psoriasis, treatment with roflumilast cream, 0.3%, compared with vehicle cream resulted in better clinical status at 8 weeks. Further research is needed to assess efficacy compared with other active treatments and to assess longer-term efficacy and safety. Trial Registration: ClinicalTrials.gov Identifiers: NCT04211363, NCT04211389.

Estimated cardiovascular benefits of bempedoic acid in patients with established cardiovascular disease.

Background and aims: Cardiovascular outcomes trials have demonstrated that lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk for future cardiovascular events. We assessed the potential cardiovascular benefits of bempedoic acid through a simulation study in patients with atherosclerotic cardiovascular disease (ASCVD) and elevated LDL-C. Methods: The validated SMART prediction model was used to estimate the baseline 10-year risk of three-point major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) in patients with ASCVD who were enrolled in four Phase 3, randomized, placebo-controlled bempedoic acid studies. The predicted change in 10-year cardiovascular risk associated with bempedoic acid was estimated for each patient based on the Cholesterol Treatment Trialists' model. Data were analyzed in two cohorts: Cohort 1 included mostly patients treated with moderate-high intensity statins, and Cohort 2 included patients who were intolerant of more than low-intensity statin. Results: A total of 2884 patients were included in Cohort 1 and 226 in Cohort 2. Weighted average baseline 10-year cardiovascular event risk was 26.1% and 31.6% for Cohorts 1 and 2, respectively. The least squares mean percent difference (95% confidence interval (CI) of the predicted absolute change in 10-year cardiovascular event risk with bempedoic acid was -3.3% (-3.7% to -2.9%) for patients in Cohort 1 and -6.0% (-7.7% to -4.3%) for patients in Cohort 2 compared with placebo (p < 0.0001 for both). Conclusions: Among patients with ASCVD who could potentially benefit from additional LDL-C lowering, our simulation predicted a lower absolute cardiovascular event risk after initiating bempedoic acid as compared with placebo.

Assessment of denosumab treatment effects and imaging response in patients with giant cell tumor of bone.

BACKGROUND: Denosumab has been shown to reduce tumor size and progression, reform mineralized bone, and increase intralesional bone density in patients with giant cell tumor of bone (GCTB); however, radiologic assessment of tumors in bone is challenging. The study objective was to assess tumor response to denosumab using three different imaging parameters in a prespecified analysis in patients with GCTB from two phase 2 studies. METHODS: The studies enrolled adults and adolescents (skeletally mature and at least 12 years of age) with radiographically measurable GCTB that were given denosumab 120 mg every 4 weeks, with additional doses on days 8 and 15 of cycle 1. The proportion of patients with an objective tumor response was assessed using either Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), European Organisation for Research and Treatment of Cancer response criteria (positron emission tomography [PET] scan criteria), or inverse Choi density/size (ICDS) criteria. Target lesions were measured by computed tomography or magnetic resonance imaging (both studies), PET (study 2 only), or plain film radiograph (study 2 only). RESULTS: Most patients (71.6%) had an objective tumor response by at least one response criteria. Per RECIST, 25.1% of patients had a response; per PET scan criteria, 96.2% had a response; per ICDS, 76.1% had a response. 68.5% had an objective tumor response ≥ 24 weeks. Using any criteria, crude incidence of response ranged from 56% (vertebrae/skull) to 91% (lung/soft tissue), and 98.2% had tumor control ≥ 24 weeks. Reduced PET avidity appeared to be an early sign of response to denosumab treatment. CONCLUSION: Modified PET scan criteria and ICDS criteria indicate that most patients show responses and higher benefit rates than modified RECIST, and therefore may be useful for early assessment of response to denosumab. TRIAL REGISTRATION: ClinicalTrials.gov Clinical Trials Registry NCT00396279 (retrospectively registered November 6, 2006) and NCT00680992 (retrospectively registered May 20, 2008).

Effect of ventilation velocity on hexavalent chromium and isocyanate exposures in aircraft paint spraying.

Exposure control system performance was evaluated during aircraft paint spraying at a military facility. Computational fluid dynamics (CFD) modeling, tracer gas testing, and exposure monitoring examined contaminant exposure vs. crossflow ventilation velocity. CFD modeling using the RNG k-ϵ turbulence model showed exposures to simulated methyl isobutyl ketone of 294 and 83.6 ppm, as a spatial average of five worker locations, for velocities of 0.508 and 0.381 m/s (100 and 75 fpm), respectively. In tracer gas experiments, observed supply/exhaust velocities of 0.706/0.503 m/s (136/99 fpm) were termed full-flow, and reduced velocities were termed 3/4-flow and half-flow. Half-flow showed higher tracer gas concentrations than 3/4-flow, which had the lowest time-averaged concentration, with difference in log means significant at the 95% confidence level. Half-flow compared to full-flow and 3/4-flow compared to full-flow showed no statistically significant difference. CFD modeling using these ventilation conditions agreed closely with the tracer results for the full-flow and 3/4-flow comparison, yet not for the 3/4-flow and half-flow comparison. Full-flow conditions at the painting facility produced a velocity of 0.528 m/s (104 fpm) midway between supply and exhaust locations, with the supply rate of 94.4 m3/s (200,000 cfm) exceeding the exhaust rate of 68.7 m3/s (146,000 cfm). Ventilation modifications to correct this imbalance created a midhangar velocity of 0.406 m/s (80.0 fpm). Personal exposure monitoring for two worker groups-sprayers and sprayer helpers ("hosemen")-compared process duration means for the two velocities. Hexavalent chromium (Cr[VI]) exposures were 500 vs. 360 µg/m3 for sprayers and 120 vs. 170 µg/m3 for hosemen, for 0.528 m/s (104 fpm) and 0.406 m/s (80.0 fpm), respectively. Hexamethylene diisocyanate (HDI) monomer means were 32.2 vs. 13.3 µg/m3 for sprayers and 3.99 vs. 8.42 µg/m3 for hosemen. Crossflow velocities affected exposures inconsistently, and local work zone velocities were much lower. Aircraft painting contaminant control is accomplished better with the unidirectional crossflow ventilation presented here than with other observed configurations. Exposure limit exceedances for this ideal condition reinforce continued use of personal protective equipment.

"A Baby Was an Added Burden": Predictors and Consequences of Unintended Pregnancies for Female Sex Workers in Mombasa, Kenya: A Mixed-Methods Study.

INTRODUCTION: Female sex workers (FSW) have high rates of unintended pregnancy, sexually transmitted infections including HIV, and other adverse sexual and reproductive health outcomes. Few services for FSWs include contraception. This mixed-methods study aimed to determine the rate, predictors and consequences of unintended pregnancy among FSWs in Mombasa, Kenya. METHODS: A prospective cohort study of non-pregnant FSWs was conducted. Quantitative data were collected quarterly, including a structured questionnaire and testing for pregnancy and HIV. Predictors of unintended pregnancy were investigated using multivariate logistic regression. Qualitative data were gathered through focus group discussions and in-depth interviews with FSWs who became pregnant during the study, and interviews with five key informants. These data were transcribed, translated and analysed thematically. RESULTS: Four hundred women were enrolled, with 92% remaining in the cohort after one year. Fifty-seven percent reported using a modern contraceptive method (including condoms when used consistently). Over one-third (36%) of women were using condoms inconsistently without another method. Twenty-four percent had an unintended pregnancy during the study. Younger age, having an emotional partner and using traditional or no contraception, or condoms only, were independent predictors of unintended pregnancy. Women attributed pregnancy to forgetting to use contraception and being pressured not to by clients and emotional partners, as well as "bad luck". They described numerous negative consequences of unintended pregnancy. CONCLUSION: Modern contraceptive uptake is surprisingly low in this at-risk population, which in turn has a high rate of unintended pregnancy. The latter may result in financial hardship, social stigma, risk of abandonment, or dangerous abortion practices. FSWs face considerable barriers to the adoption of dual method contraceptive use, including low levels of control in their emotional and commercial relationships. Reproductive health services need to be incorporated into programs for sexually transmitted infections and HIV, which address the socially-determined barriers to contraceptive use.

Uterine Papillary Serous Carcinoma: A Single-Institution Review of 62 Cases.

OBJECTIVE: Uterine papillary serous carcinoma (UPSC) is a rare variant of endometrial carcinoma responsible for up to 40% of endometrial cancer deaths. Controversy remains regarding optimal adjuvant therapy for UPSC, with lack of randomized trials to date. The objective of this retrospective study was to evaluate clinicopathological factors and determine event-free survival and overall survival (OS) in patients with UPSC managed within a single institution. MATERIALS AND METHODS: Medical and pathological records between 1987 and 2004 were reviewed at the Royal Women's Hospital, Melbourne, Australia. Cox regression analysis was used to analyze effects of clinical and histopathological variables on patient survival and survival times following adjuvant therapy. Event-free survival and OS were analyzed using the Kaplan-Meier survival curve. RESULTS: Sixty-two patients were included; 96.8% were managed surgically and 56.5% were completely surgically staged. Myoinvasion was present in 72.6% (n = 45) of the patients.In patients with stage I disease, recurrence rate was 41.4% with a 5-year OS of 46%. In stage II, recurrence rate was 20% with a 5-year OS of 67%. In stage III, recurrence rate was 58.8% with a 5-year OS of 34%. In stage IV, recurrence rate was 71.4% with a 5-year OS of 29%.There was no significant difference in survival based on the presence of positive peritoneal cytology, positive lymphovascular space invasion or positive lymph nodes at diagnosis, and no significant difference in survival based on the type of adjuvant therapy administered. Depth of myometrial invasion was a significant determinant of poor prognosis (P = 0.027). CONCLUSIONS: Uterine papillary serous carcinoma is an aggressive variant of endometrial cancer associated with a high proportion of advanced-stage disease at diagnosis, high recurrence rates, and low OS. In our patients, prognosis was determined by myometrial invasion and International Federation of Gynecology and Obstetrics stage at diagnosis. Randomized trials in this area are required to clarify optimal adjuvant therapy for patients with UPSC.

Surgical downstaging in an open-label phase II trial of denosumab in patients with giant cell tumor of bone.

BACKGROUND: Surgical resection with curative intent for giant cell tumor of bone (GCTB) may be associated with severe morbidity. This interim analysis evaluated reduction in surgical invasiveness after denosumab treatment in patients with resectable GCTB. METHODS: Patients with primary or recurrent GCTB, for whom the initially planned surgery was associated with functional compromise or morbidity, received denosumab 120 mg subcutaneously every 4 weeks (additional doses on days 8 and 15 of the first cycle). Planned and actual GCTB-related surgical procedures before and after denosumab treatment were reported. Patients were followed for surgical outcome, adverse events, and recurrence following resection. RESULTS: Overall, 222 patients were evaluable for surgical downstaging (54 % were women; median age 34 years). Lesions (67 % primary and 33 % recurrent) were located in the axial (15 %) and appendicular skeleton (85 %). At the data cutoff date, most patients had not yet undergone surgery (n = 106; 48 %) or had a less morbid procedure (n = 84; 38 %) than originally planned. Median (interquartile range) time on denosumab was 19.5 (12.4-28.6) months for the 106 patients who had not undergone surgery and were continuing on monthly denosumab. Native joint preservation was 96 % (n = 24/25) for patients with planned joint/prosthesis replacement and 86 % (n = 30/35) for patients with planned joint resection/fusion. Of the 116 patients who had surgery (median postsurgical follow-up 13.0 [8.5-17.9] months), local recurrence occurred in 17 (15 %) patients. CONCLUSION: For patients with resectable GCTB, neoadjuvant denosumab therapy resulted in beneficial surgical downstaging, including either no surgery or a less morbid surgical procedure.

The role of denosumab in the prevention of hypercalcaemia of malignancy in cancer patients with metastatic bone disease.

BACKGROUND: We compared the activity of denosumab with zoledronic acid for delaying or preventing hypercalcaemia of malignancy (HCM) in patients with advanced cancer and bone metastases or with multiple myeloma. METHODS: Patient-level data were combined from two identically designed, randomised, double-blind, active-controlled, phase III trials of advanced cancer patients with breast cancer and other solid tumours (excluding breast or prostate cancer) or multiple myeloma. End-points included time to first on-study HCM, time to first and subsequent on-study HCM, proportion of patients experiencing HCM and proportion of patients experiencing recurrent HCM. RESULTS: Denosumab significantly delayed the time to first on-study HCM, representing a 37% reduction in the hazard ratio (HR) compared with zoledronic acid (HR, 0.63; 95% confidence interval (CI): 0.41-0.98; P = 0.042) and reduced the risk of developing recurrent HCM (time to first and subsequent on-study HCM) by 52% (rate ratio, 0.48; 95% CI: 0.29-0.81; P = 0.006). The median time on study was 12.9 months. Fewer patients receiving denosumab compared with zoledronic acid experienced an HCM event (1.7% versus 2.7%; P = 0.028). Of the 84 patients experiencing an HCM event, 40% of those receiving zoledronic acid experienced >1 event of HCM compared with 31% of those receiving denosumab. CONCLUSION: Denosumab treatment was more efficacious than treatment with zoledronic acid in delaying or preventing HCM in advanced cancer patients with breast cancer, other solid tumours or multiple myeloma.

Echocardiographic Ramp test for continuous-flow left ventricular assist devices: do loading conditions matter?

OBJECTIVES: This study investigated whether continuous AI and/or elevated mean arterial pressure (MAP) were associated with false positive results for flow obstruction in echocardiographic ramp speed tests in patients with a continuous-flow left ventricular assist device. BACKGROUND: Failure to reduce the left ventricular end-diastolic diameter (LVEDD) with increasing device speeds in a ramp test is predictive of pump obstruction. Aortic insufficiency (AI) or increased MAP can diminish the ability to unload the left ventricle. METHODS: LVEDD was plotted against device speed, and a linear function slope was calculated. A flat LVEDD slope (≥-0.16) was considered abnormal (suggestive of obstruction). Ramp test results were compared in patients with or without either AI or increased MAP at baseline speed, and receiver-operator characteristic (ROC) curves were constructed for predictors of device obstruction. Device thrombosis was confirmed by direct visualization of clot at explantation or on inspection by the manufacturer. RESULTS: Of 78 ramp tests (55 patients), 36 were abnormal (18 true positive, 18 false positive), and 42 were normal (37 true negative, 5 false negative). In patients with AI, LVEDD slope was -0.14 ± 0.17, which was consistent with device obstruction (vs. -0.25 ± 0.11 in patients without AI; p < 0.001), despite no difference in mean lactate dehydrogenase concentration between the 2 groups (1,301 ± 1,651 U/l vs. 1,354 ± 1,365 U/l; p = 0.91). Area under the ROC curve (AUC) for LVEDD slope was 0.76 and improved to 0.88 after removal of patients with AI from the study. LVEDD slope in patients with MAP ≥85 mm Hg was similar to that for device obstruction (-0.18 ± 0.07) and was abnormal in 6 of the 12 ramp tests performed. Combining LVEDD slope with lactate dehydrogenase concentration increased the AUC to 0.96 as an indicator of device obstruction. CONCLUSIONS: Abnormal loading conditions due to AI or elevated MAP may result in false positive ramp tests.

Anti-factor Xa and activated partial thromboplastin time measurements for heparin monitoring in mechanical circulatory support.

OBJECTIVES: This study investigated the relationship between anti-factor Xa (anti-FXa) and activated partial thromboplastin time (aPTT) for monitoring intravenous unfractionated heparin (IV-UFH) in patients with continuous-flow left ventricular assist devices (CF-LVADs). BACKGROUND: CF-LVADs have become mainstream therapy for patients with advanced heart failure. Thromboembolic events, device thrombosis, and bleeding continue to be a challenge with this technology. Adequate anticoagulation is required to prevent these adverse events. METHODS: A prospective study of consecutive patients implanted with a CF-LVAD was conducted. Paired samples were considered concordant if aPTT values fell into expected ranges for subtherapeutic, therapeutic, and supratherapeutic anti-FXa levels. Heparin dosing was on the basis of anti-Xa levels. RESULTS: A total of 340 paired values from 38 patients were evaluated. Anti-FXa and aPTT were discordant in 253 samples (74.4%), with a high degree of variability in aPTT for any given anti-FXa level (r(2) = 0.57). Results were discordant in 104 samples (63.8%) from patients undergoing bridging therapy with warfarin and in 149 samples (84.2%) from patients with device obstruction and/or hemolysis (p < 0.001). The most common pattern of discordance was a supratherapeutic aPTT value despite a therapeutic anti-FXa level (49.1% for bridging vs. 75.8% for device obstruction and/or hemolysis; p < 0.001). CONCLUSIONS: Levels of aPTT were disproportionately prolonged relative to the corresponding anti-FXa levels in CF-LVAD patients, particularly those with device obstruction. Hemolysis and warfarin administration may falsely elevate aPTT, resulting in overestimation of heparin concentration and under-anticoagulation. Use of aPTT and anti-FXa to guide heparin therapy may lead to different estimates of heparin concentration in the same patient.

Effects of denosumab on pain and analgesic use in giant cell tumor of bone: interim results from a phase II study.

BACKGROUND: Giant cell tumor of bone (GCTB) is an aggressive primary osteolytic tumor. GCTB often involves the epiphysis, usually causing substantial pain and functional disability. Denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κΒ ligand (RANKL), is an effective treatment option for patients with advanced GCTB. This analysis of data from an ongoing, open-label study describes denosumab's effects on pain and analgesic use in patients with GCTB. MATERIAL AND METHODS: Patients with unresectable disease (e.g. sacral or spinal GCTB, or multiple lesions including pulmonary metastases) were enrolled into Cohort 1 (N = 170), and patients with resectable disease whose planned surgery was associated with severe morbidity (e.g. joint resection, limb amputation, or hemipelvectomy) were enrolled into Cohort 2 (N = 101). Patients received denosumab (120 mg) subcutaneously every four weeks, with additional doses on study days 8 and 15. Patients assessed worst pain severity with the Brief Pain Inventory - Short Form (BPI-SF) at baseline, at each visit for the first six months, and every three months thereafter. RESULTS: Clinically relevant pain improvement was reported by 29% of patients in Cohort 1 and 35% in Cohort 2 during week 1 and by ≥ 50% of patients in each cohort at each study visit from months 2-30. Median time to clinically relevant improvement was 30 (95% CI 16, 57) days in Cohort 1 and 15 (95% CI 15, 29) days in Cohort 2. Results in patients with moderate/severe pain at baseline were similar. Fewer than 30% of patients in Cohort 1 and 10% in Cohort 2 experienced clinically relevant pain worsening at any visit through 27 months. Most patients had no/low analgesic use during the study. CONCLUSION: Most patients treated with denosumab experienced clinically relevant decreases in pain within two months.

Delaying skeletal-related events in a randomized phase 3 study of denosumab versus zoledronic acid in patients with advanced cancer: an analysis of data from patients with solid tumors.

PURPOSE: Bone complications of metastatic disease, including skeletal-related events (SREs), impair patients' functioning and quality of life. In a randomized, phase 3 trial of 1,776 patients with metastases from solid tumors (except breast or prostate) or multiple myeloma, denosumab was non-inferior to zoledronic acid (ZA) in delaying or preventing SREs. This ad hoc analysis reports outcomes in the subgroup of 1,597 patients with solid tumors, excluding patients with multiple myeloma. METHODS: Patients received monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg, adjusted for creatinine clearance, with calcium and vitamin D supplementation recommended. Endpoints included times to first on-study SRE, first-and-subsequent SREs, and pain worsening. RESULTS: Denosumab significantly delayed time to first on-study SRE compared with ZA (HR, 0.81; 95 % CI, 0.68-0.96) and time to first-and-subsequent SREs (RR, 0.85; 95 % CI, 0.72-1.00). Denosumab also significantly delayed time to development of moderate or severe pain (HR, 0.81; 95 % CI, 0.66-1.00), pain worsening (HR, 0.83; 95 % CI, 0.71-0.97), and worsening pain interference in patients with no/mild baseline pain (HR, 0.77; 95 % CI, 0.61-0.96). Adverse event rates were 96 % in both groups. Grade 3 or 4 hypocalcemia, mostly without clinical sequelae, was more frequent in denosumab-treated patients (denosumab 4 %, ZA 2 %). Osteonecrosis of the jaw occurred infrequently (denosumab 0.8 %, ZA 1.1 %). CONCLUSIONS: Denosumab was more effective in delaying or preventing SREs in patients with bone metastases from solid tumors and also prevented pain progression compared to ZA in this ad hoc analysis.

Reactive oxygen species from human astrocytes induced functional impairment and oxidative damage.

Reactive oxygen species (ROS) have been shown to be a contributor to aging and disease. ROS also serve as a trigger switch for signaling cascades leading to corresponding cellular and molecular events. In the central nervous system (CNS), microglial cells are likely the main source of ROS production. However, activated astrocytes also appear to be capable of generating ROS. In this study we investigated ROS production in human astrocytes stimulated with interleukin (IL)-1ß and interferon (IFN)-γ and its potential harmful effects. Although IFN-γ alone had no effect, it potentiated IL-1ß-induced ROS production in a time-dependent manner. One of the sources of ROS in IL-1ß-activated astrocytes was from increased superoxide production in mitochondria accompanied by enhanced manganese superoxide dismutase and inhibited catalase expression. NADPH oxidase (NOX) may also contribute to ROS production as astrocytes express NOX isoforms. Glutamate uptake, which represents one of the most important methods of astrocytes to prevent excitotoxicity, was down-regulated in IL-1ß-activated astrocytes, and was further suppressed in the presence of IFN-γ; IFN-γ itself exerted minimal effect. Elevated levels of 8-isoprostane in IL-1ß ± IFN-γ-activated human astrocytes indicate downstream lipid peroxidation. Pretreatment with diphenyleneiodonium abolished the IL-1ß ± IFN-γ-induced ROS production, restored glutamate uptake function and reduced 8-isoprostane to near control levels suggesting that ROS contributes to the dysfunction of activated astrocytes. These results support the notion that dampening activated human astrocytes to maintain the redox homeostasis is vital to preserve their neuroprotective potential in the CNS.

Darbepoetin alfa impact on health status in diabetes patients with kidney disease: a randomized trial.

BACKGROUND AND OBJECTIVES: Quality of life (QOL) is markedly impaired in patients with anemia, diabetes mellitus, and chronic kidney disease. Limited data exist regarding the effect of anemia treatment on patient perceptions. The objectives were to determine the longitudinal impact of anemia treatment on quality of life in patients with diabetes and chronic kidney disease and to determine the predictors of baseline and change in QOL. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In a large, double blind study, patients with type 2 diabetes mellitus, nondialysis chronic kidney disease (estimated GFR, 20 to 60 ml/min per 1.73 m(2)), and anemia (hemoglobin 10.4 g/dl) were randomized to darbepoetin alfa or placebo. QOL was measured with Functional Assessment of Cancer Therapy-Fatigue, Short Form-36, and EuroQol scores over 97 weeks. RESULTS: Patients randomized to darbepoetin alfa reported significant improvements compared with placebo patients in Functional Assessment of Cancer Therapy-Fatigue, and EuroQol scores visual analog scores, persisting through 97 weeks. No consistent differences in Short Form-36 were noted. Consistent predictors of worse change scores include lower activity level, older age, pulmonary disease, and duration of diabetes. Interim stroke had a substantial negative impact on fatigue and physical function. CONCLUSION: Darbepoetin alfa confers a consistent, but small, improvement in fatigue and overall quality of life but not in other domains. These modest QOL benefits must be considered in the context of neutral overall effect and increased risk of stroke in a small proportion of patients. Patient's QOL and potential treatment risk should be considered in any treatment decision.

Use and prescribing patterns for erythropoiesis-stimulating agents in inpatient and outpatient hospital settings.

PURPOSE: Erythropoiesis-stimulating agent (ESA) use in the outpatient and inpatient settings through pharmacist-conducted, hospital-based chart audits is examined and discussed. METHODS: Data from four hospital chart audits conducted in 250 hospitals between October 2005 and July 2006 were pooled for analyses. Eligible hospitals were categorized by ESA sales volume, with approximately equal numbers randomly selected from each decile. The last five inpatients and outpatients within each specified month receiving either darbepoetin alfa or epoetin alfa were evaluated. Study variables by setting included ESA use, prescriber specialty, and dosage regimen. RESULTS: The most common hospital locations of ESA administration were a cancer center in the outpatient setting (49%) and general medicine (57%) in the inpatient setting. ESA prescribers were most commonly hematologists and oncologists in the outpatient setting, and nephrologists were the most common prescribers in the inpatient setting. In the outpatient analysis, 2155 patients were prescribed darbepoetin alfa and 3106 were prescribed epoetin alfa. The predominant administration frequencies were every two weeks and once weekly for darbepoetin alfa, and once weekly for epoetin alfa. In the inpatient analysis, 1633 patients were prescribed darbepoetin alfa and 3231 were prescribed epoetin alfa. The predominant administration frequencies were once weekly for darbepoetin alfa and once weekly and three times weekly for epoetin alfa. Common uses for both ESAs were chemotherapy-induced anemia (outpatient setting) and anemia of end-stage renal disease with chronic dialysis (inpatient setting). There was considerable variability in ESA dosages and administration frequencies in both settings within all patient groups when analyzed by specified use. CONCLUSION: ESA use differed between outpatient and inpatient settings in indication, frequency of administration, and specialty of the prescriber.

An evaluation of conditions that may affect the performance of houseboat exhaust stacks in prevention of carbon monoxide poisonings from generators.

National Institute for Occupational Safety and Health (NIOSH) researchers evaluated two exhaust stack designs for reducing carbon monoxide (CO) exposures from gasoline-powered generator exhaust on houseboats. Tests were conducted (a) after dark, (b) in high-temperature and high-humidity environments, (c) during temperature inversions, (d) under various generator loads, and (e) at different houseboat trim angles. Two different designs of houseboat exhaust stacks were evaluated and compared with the side-exhaust configuration, which is standard on many houseboats. The two designs were flagpole and vertical stack. Both exhaust stacks performed dramatically better than the standard water level, side-exhaust configuration. The highest mean CO concentrations on the upper and lower decks of the houseboat with the vertical exhaust stack were 27 ppm and 17 ppm. The highest mean CO concentrations on the upper and lower decks of the houseboat with the modified flagpole stack were 5 ppm and 2 ppm. These findings are much lower than the 67 ppm and 341 ppm for the highest mean CO concentrations found on the upper and lower decks of houseboats having the usual side-exhausted configuration. The NIOSH evaluation also indicated that high-temperature and high-humidity levels, temperature inversions, generator loading, and houseboat trim angles had little effect on the exhaust stack performance. It also demonstrated the importance of proper design and installation of exhaust stacks to ensure that all exhaust gases are released through the stack. Based on the results of this work, NIOSH investigators continue to recommend that houseboat manufacturers, rental companies, and owners retrofit their gasoline-powered generators with exhaust stacks to reduce the hazard of CO poisoning and death to individuals on or near the houseboat.