We have studied a three-drug combination with cyclophosphamide, bortezomib and dexamethasone (CyBorD) on a 28-day cycle in the treatment of newly diagnosed multiple myeloma (MM) patients to assess ...response and toxicity. The primary endpoint of response was evaluated after four cycles. Thirty-three newly diagnosed, symptomatic patients with MM received bortezomib 1.3 mg/m(2) intravenously on days 1, 4, 8 and 11, cyclophosphamide 300 mg/m(2) orally on days 1, 8, 15 and 22 and dexamethasone 40 mg orally on days 1-4, 9-12 and 17-20 on a 28-day cycle for four cycles. Responses were rapid with a mean 80% decline in the sentinel monoclonal protein at the end of two cycles. The overall intent to treat response rate (>or= partial response) was 88%, with 61% of very good partial response or better (>or=VGPR) and 39% of complete/near complete response (CR/nCR). For the 28 patients who completed all four cycles of therapy, the CR/nCR rate was 46% and VGPR rate was 71%. All patients undergoing stem cell harvest had a successful collection. Twenty-three patients underwent stem cell transplantation (SCT) and are evaluable through day 100 with CR/nCR documented in 70% and >or=VGPR in 74%. In conclusion, CyBorD produces a rapid and profound response in patients with newly diagnosed MM with manageable toxicity.
The Cassini Ultraviolet Imaging Spectrograph (UVIS) observed an occultation of the Sun by the water vapor plume at the south polar region of Saturn's moon Enceladus. The Extreme Ultraviolet (EUV) ...spectrum is dominated by the spectral signature of H2O gas, with a nominal line‐of‐sight column density of 0.90 ± 0.23 × 1016 cm−2 (upper limit of 1.0 × 1016 cm−2). The upper limit for N2 is 5 × 1013 cm−2, or <0.5% in the plume; the lack of N2 has significant implications for models of the geochemistry in Enceladus' interior. The inferred rate of water vapor injection into Saturn's magnetosphere is ∼200 kg/s. The calculated values of H2O flux from three occultations observed by UVIS have a standard deviation of 30 kg/s (15%), providing no evidence for substantial short‐term variability. Collimated gas jets are detected in the plume with Mach numbers of 5–8, implying vertical gas velocities that exceed 1000 m/sec. Observations at higher altitudes with the Cassini Ion Neutral Mass Spectrometer indicate correlated structure in the plume. Our results support the subsurface liquid model, with gas escaping and being accelerated through nozzle‐like channels to the surface, and are consistent with recent particle composition results from the Cassini Cosmic Dust Analyzer.
Key Points
N2 upper limit
Mach number of jets ranges from 5 to 8, more collimated than previous estimate
Flux of water vapor stable over last 6 years at 200 kg/sec
To evaluate the effects of a high-fat and low-fat diet on taste sensitivity to oleic acid (C18:1) in lean and overweight/obese (OW/OB) subjects.
Randomized cross-over dietary intervention involving ...the consumption of a high-fat (>45% fat) and low-fat (<20% fat) diet, both consumed over a 4-week period.
A total of 19 lean, mean age 33±13 years, mean body mass index (BMI) 23.2±2.2 kg m(-2) and 12 OW/OB, mean age 39.5±3 years, mean BMI 28±2.6 kg m(-2), subjects participated in the study, which measured taste thresholds for C18:1, fat perception and hedonic ratings for regular (RF) and lowered-fat (LF) foods before, and following consumption of a high- and low-fat diet.
Consumption of the low-fat diet increased taste sensitivity to C18:1 among lean and OW/OB subjects (P<0.05) and increased the subjects ability to perceive small differences in the fat content of custard (P=0.05). Consumption of the high-fat diet significantly decreased taste sensitivity to C18:1 among lean subjects (P<0.05), with no change in sensitivity among OW/OB persons (P=0.609). The hedonic ratings for several RF and LF foods differed following the diets.
Alterations in the fat content of the diet modulated taste sensitivity to C18:1 among lean subjects, which was increased following a 4-week period of fat restriction and attenuated following the high-fat diet. The failure of the high-fat diet to alter fatty acid taste thresholds among OW/OB subjects suggests that these individuals were 'adapted' to high-fat exposure, perhaps because of differences in habitual fat consumption. Taken together, these data suggest that excessive dietary fat attenuates nutrient sensing epithelia response in the oral cavity, which could be associated with changes in diet and weight status.
The present study aimed to compare a range of cooling methods possibly utilised by occupational workers, focusing on their effect on body temperature, perception and manual dexterity.
Ten male ...participants completed eight trials involving 30 min of seated rest followed by 30 min of cooling or control of no cooling (CON) (34°C, 58% relative humidity). The cooling methods utilised were: ice cooling vest (CV0), phase change cooling vest melting at 14°C (CV14), evaporative cooling vest (CVEV), arm immersion in 10°C water (AI), portable water-perfused suit (WPS), heliox inhalation (HE) and ice slushy ingestion (SL). Immediately before and after cooling, participants were assessed for fine (Purdue pegboard task) and gross (grip and pinch strength) manual dexterity. Rectal and skin temperature, as well as thermal sensation and comfort, were monitored throughout.
Compared with CON, SL was the only method to reduce rectal temperature (P = 0.012). All externally applied cooling methods reduced skin temperature (P<0.05), though CV0 resulted in the lowest skin temperature versus other cooling methods. Participants felt cooler with CV0, CV14, WPS, AI and SL (P<0.05). AI significantly impaired Purdue pegboard performance (P = 0.001), but did not affect grip or pinch strength (P>0.05).
The present study observed that ice ingestion or ice applied to the skin produced the greatest effect on rectal and skin temperature, respectively. AI should not be utilised if workers require subsequent fine manual dexterity. These results will help inform future studies investigating appropriate pre-cooling methods for the occupational worker.
Aim: To describe gut colonization in preterm infants using standard culture and 16S gene rRNA profiling, exploring differences in healthy infants and those who developed NEC/late onset sepsis (LOS).
...Methods: Ninety‐nine stools from 38 infants of median 27‐week gestation were cultured; 44 stools from 27 infants had their microbial profiles determined by 16S. Ordination analyses explored effects of patient variables on gut communities.
Results: Standard microbiological culture identified a mean of two organisms (range 0–7), DGGE 12 (range 3–18) per patient. Enterococcus faecalis and coagulase negative staphylococci (CONS) were most common by culture (40% and 39% of specimens). Meconium was not sterile. No fungi were cultured. Bacterial community structures in infants with NEC and LOS differed from healthy infants. Infants who developed NEC carried more CONS (45% vs 30%) and less Enterococcus faecalis (31% vs 57%). 16S identified Enterobacter and Staphylococcus presence associated with NEC/LOS, respectively.
Conclusions: Important differences were found in the gut microbiota of preterm infants who develop NEC/LOS. The relationship of these changes to current practices in neonatal intensive care requires further exploration.
Aim
Determine the impact of beneficial phytochemicals on diversity and abundance of the gut microbiome in the honey bee (Apis mellifera).
Methods and Results
Eight‐day‐old honey bee workers were fed ...25 ppm of phytochemical (caffeine, gallic acid, p‐coumaric acid or kaempferol) in 20% sucrose. Guts of bees collected at 3 and 6 days were excised and subjected to next‐generation sequencing for bacterial 16S and fungal ITS regions. Although phytochemical supplementation fostered gut microbial diversity and abundance, the patterns differed between phytochemicals and there was a temporal stabilization of the bacterial community. While bacterial and fungal communities responded differently, all phytochemical treatments displayed increased abundance of the most represented bacterial genera, Snodgrassella sp. and Lactobacillus sp.
Conclusions
Phytochemical supplementation improves gut microbial diversity and abundance, reiterating the need for diverse habitats that provide bees with access to pollen and nectar rich in these micronutrients. Diverse gut microbiota can provide a strong line of defense for bees against biotic stressors while improving worker bee lifespan.
Significance and Impact of the Study
This is the first report on the impact of phytochemical supplementation on gut microbiota in honey bees and these findings have implications for strategic hive management through standardization of effective phytochemical and probiotic feed supplements.
Aims The aim of this study was to assess the current evidence relating to the benefits of virtual reality (VR) simulation in orthopaedic surgical training, and to identify areas of future research. ...Materials and Methods A literature search using the MEDLINE, Embase, and Google Scholar databases was performed. The results' titles, abstracts, and references were examined for relevance. Results A total of 31 articles published between 2004 and 2016 and relating to the objective validity and efficacy of specific virtual reality orthopaedic surgical simulators were identified. We found 18 studies demonstrating the construct validity of 16 different orthopaedic virtual reality simulators by comparing expert and novice performance. Eight studies have demonstrated skill acquisition on a simulator by showing improvements in performance with repeated use. A further five studies have demonstrated measurable improvements in operating theatre performance following a period of virtual reality simulator training. Conclusion The demonstration of 'real-world' benefits from the use of VR simulation in knee and shoulder arthroscopy is promising. However, evidence supporting its utility in other forms of orthopaedic surgery is lacking. Further studies of validity and utility should be combined with robust analyses of the cost efficiency of validated simulators to justify the financial investment required for their use in orthopaedic training. Cite this article: Bone Joint J 2018;100-B:559-65.
Margetuximab is an anti-HER2 antibody that binds with elevated affinity to both the lower and higher affinity forms of CD16A, an Fc-receptor important for antibody dependent cell-mediated ...cytotoxicity (ADCC) against tumor cells. A Phase 1 study was initiated to evaluate the toxicity profile, maximum tolerated dose (MTD), pharmacokinetics, and antitumor activity of margetuximab in patients with HER2-overexpressing carcinomas.
Patients with HER2-positive breast or gastric cancer, or other carcinomas that overexpress HER2, for whom no standard therapy was available, were treated with margetuximab by intravenous infusion at doses of 0.1–6.0 mg/kg for 3 of every 4 weeks (Regimen A) or once every 3 weeks (10–18 mg/kg) (Regimen B).
Sixty-six patients received margetuximab (34 patients for Regimen A and 32 patients for Regimen B). The MTD was not reached for either regimen. Treatment was well-tolerated, with mostly Grade 1 and 2 toxicities consisting of constitutional symptoms such as pyrexia, nausea, anemia, diarrhea, and fatigue. Among 60 response-evaluable patients, confirmed partial responses and stable disease were observed in 7 (12%) and 30 (50%) patients, respectively; 26 (70%) of these patients had received prior HER2-targeted therapy. Tumor reductions were observed in over half (18/23, 78%) of response-evaluable patients with breast cancer including durable (>30 weeks) responders.Ex vivo analyses of patient peripheral blood mononuclear cell samples confirmed the ability of margetuximab to support enhanced ADCC compared with trastuzumab.
Margetuximab was well-tolerated and has promising single-agent activity. Further development efforts of margetuximab as single agent and in combination with other therapeutic agents are ongoing.
NCT01148849.
Summary
Background Multiple questionnaires to screen for psoriatic arthritis (PsA) have been developed but the optimal screening questionnaire is unknown.
Objectives To compare three PsA screening ...questionnaires in a head‐to‐head study using CASPAR (the Classification Criteria for Psoriatic Arthritis) as the gold standard.
Methods This study recruited from 10 U.K. secondary care dermatology clinics. Patients with a diagnosis of psoriasis, not previously diagnosed with PsA, were given all three questionnaires. All patients who were positive on any questionnaire were invited for a rheumatological assessment. Receiver operating characteristic (ROC) curves were used to compare the sensitivity, specificity and area under the curve of the three questionnaires according to CASPAR criteria.
Results In total, 938 patients with psoriasis were invited to participate and 657 (70%) patients returned the questionnaires. One or more questionnaires were positive in 314 patients (48%) and 195 (62%) of these patients attended for assessment. Of these, 47 patients (24%) were diagnosed with PsA according to the CASPAR criteria. The proportion of patients with PsA increased with the number of positive questionnaires (one questionnaire, 19·1%; two, 34·0%; three, 46·8%). Sensitivities and specificities for the three questionnaires, and areas under the ROC curve were, respectively: Psoriatic Arthritis Screening Evaluation (PASE), 74·5%, 38·5%, 0·594; Psoriasis Epidemiology Screening Tool (PEST), 76·6%, 37·2%, 0·610; Toronto Psoriatic Arthritis Screen (ToPAS), 76·6%, 29·7%, 0·554. The majority of patients with a false positive response had degenerative or osteoarthritis.
Conclusion Although the PEST and ToPAS questionnaires performed slightly better than the PASE questionnaire at identifying PsA, there is little difference between these instruments. These screening tools identify many cases of musculoskeletal disease other than PsA.
What’s already known about this topic?
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A number of screening questionnaires have been developed to detect psoriatic arthritis in people with psoriasis.
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Each questionnaire has shown good and largely equivalent performance, in terms of specificity and sensitivity, in the development cohorts.
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What is needed is a head‐to‐head study in a new cohort of patients with psoriasis.
What does this study add?
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Each of the questionnaires performed worse in this new cohort of patients in secondary care, with no significant differences between them.
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Both sensitivity and specificity were worse, although the study design was likely to underestimate the specificity and overestimate the sensitivity.
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Screening questionnaires such as these will detect other musculoskeletal diseases in addition to psoriatic arthritis and additional information may be needed to enhance their specificity.
Desensitized patients are at high risk of developing acute antibody‐mediated rejection (AMR). In most cases, the rejection episodes are mild and respond to a short course of plasmapheresis (PP) / ...low‐dose IVIg treatment. However, a subset of patients experience severe AMR associated with sudden onset oliguria. We previously described the utility of emergent splenectomy in rescuing allografts in patients with this type of severe AMR. However, not all patients are good candidates for splenectomy. Here we present a single case in which eculizumab, a complement protein C5 antibody that inhibits the formation of the membrane attack complex (MAC), was used combined with PP/IVIg to salvage a kidney undergoing severe AMR. We show a marked decrease in C5b‐C9 (MAC) complex deposition in the kidney after the administration of eculizumab.
Eculizumab, a complement C5 inhibitor, was used in a kidney transplant patient undergoing severe antibody mediated rejection, demonstrating effective blockade the membrane attack complex (MAC) and associated with subsequent complete recovery of renal function.
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