Perioperative management of pediatric patients undergoing juvenile angiofibroma resection. A case series and educational review highlighting patient blood management.

BACKGROUND: Juvenile nasopharyngeal angiofibromas are one of the most enigmatic, bloody tumors encountered by otorhinolarygnologists, head and neck surgeons, neurosurgeons, and anesthesiologists. Juvenile nasopharyngeal angiofibromas are rare, benign, highly vascular tumors with a propensity towards aggressive local invasion. Surgery, open or endoscopic, to remove the growth is the primary treatment of choice for Juvenile nasopharyngeal angiofibromas. Historically, surgical resection was associated with massive, rapid blood loss, traditionally managed by blood product transfusion and deliberate hypotension. Preventative management employing multimodal blood conservation strategies should be an essential standard of perioperative care for patients with Juvenile nasopharyngeal angiofibromas. METHODS: We describe a contemporary and comprehensive approach in the management of patients with high grade Juvenile nasopharyngeal angiofibromas. This includes surgical strategies such as preemptive external carotid artery embolization, endoscopic surgical approach, and staged operations, as well as anesthetic strategies including antifibrinolytic therapy and acute normovolemic hemodilution. These surgeries, once synonymous with massive transfusion, may potentially be performed without allogeneic blood transfusion, or deliberate hypotension. AIMS: Using a case series, the authors introduce a contemporary approach to multimodal, multidisciplinary blood conservation strategies for Juvenile nasopharyngeal angiofibromas surgery. RESULTS: Here in the authors report on an updated contemporary perioperative clinical approach to patients with Juvenile nasopharyngeal angiofibromas. From an anesthetic perspective, we describe the successful use of normal hemodynamic goals, restrictive transfusion strategy, antifibrinolytic therapy, autologous normovolemic hemodilution, and early extubation in the care of three adolescent males with highly invasive tumors. We demonstrate that new surgical and anesthetic strategies have yielded a significant decrease in intraoperative blood loss and eliminated the need for transfusion of autologous red blood cells, which enable improved outcomes. CONCLUSIONS: The perioperative approach to elective surgery for Juvenile nasopharyngeal angiofibromas management is presented from a multidisciplinary patient blood management perspective.

Unchecked immunity: a unique case of sequential immune-related adverse events with Pembrolizumab.

BACKGROUND: Immune checkpoint inhibition has dramatically transformed the treatment of malignant melanoma. With increasing use, their unique spectrum of immune-mediated toxicity has become apparent. CASE PRESENTATION: We describe a case of sequential immune-related adverse events (irAEs) in a patient with metastatic melanoma treated with single-agent anti-programmed cell death-1 (PD-1) therapy, pembrolizumab. Although numerous cases of irAEs have been reported, sequential multi-organ involvement, including progressive atopic dermatitis, vitiligo, autoimmune nephritis, autoimmune hepatitis, and autoimmune encephalitis after cessation of therapy, has not been previously documented. CONCLUSIONS: Immunosuppression resulted in clinical remission of each irAE, highlighting the importance of vigilance for autoimmune complications in patients treated with checkpoint inhibition, even after immunotherapy cessation.

From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients.

The concept of adaptive licensing (AL) has met with considerable interest. Yet some remain skeptical about its feasibility. Others argue that the focus and name of AL should be broadened. Against this background of ongoing debate, we examine the environmental changes that will likely make adaptive pathways the preferred approach in the future. The key drivers include: growing patient demand for timely access to promising therapies, emerging science leading to fragmentation of treatment populations, rising payer influence on product accessibility, and pressure on pharma/investors to ensure sustainability of drug development. We also discuss a number of environmental changes that will enable an adaptive paradigm. A life-span approach to bringing innovation to patients is expected to help address the perceived access vs. evidence trade-off, help de-risk drug development, and lead to better outcomes for patients.

Accelerated access to innovative medicines for patients in need.

There is broad agreement among health-care stakeholders that more must be done to ensure that patients have timely access to new and innovative medicines. Assuming that industry will continue to develop such medicines at a sustainable rate, regulators and payers become the gatekeepers. Regulators, starting in the late 1980s/early 1990s, and, more recently, payers have implemented a variety of early-access pathways or initiatives, and this practice is continuing even today. This article describes the specific approaches that have been taken in four economically developed regions, reviews their success rates, and suggests possible new directions.

Characterization of Peroxidase Changes in Tolerant and Susceptible Soybeans Challenged by Soybean Aphid (Hemiptera: Aphididae).

Changes in protein content, peroxidase activity, and isozyme profiles in response to soybean aphid feeding were documented at V1 (fully developed leaves at unifoliate node, first trifoliate leaf unrolled) and V3 (fully developed leaf at second trifoliate node, third trifoliate leaf unrolled) stages of soybean aphid-tolerant (KS4202) and -susceptible (SD76R) soybeans. Protein content was similar between infested and control V1 and V3 stage plants for both KS4202 and SD76R at 6, 16, and 22 d after aphid introduction. Enzyme kinetics studies documented that control and aphid-infested KS4202 V1 stage and SD76R V1 and V3 stages had similar levels of peroxidase activity at the three time points evaluated. In contrast, KS4202 aphid-infested plants at the V3 stage had significantly higher peroxidase activity levels than control plants at 6 and 22 d after aphid introduction. The differences in peroxidase activity observed between infested and control V3 stage KS4202 plants at these two time points suggest that peroxidases may be playing multiple roles in the tolerant plant. Native gels stained for peroxidase were able to detect differences in the isozyme profiles of aphid-infested and control plants for both KS4202 and SD76R.

Legal foundations of adaptive licensing.

In April 2012, MIT's Center for Biomedical Innovation and the European Medicines Agency (EMA) cosponsored a workshop on legal foundations of adaptive pharmaceuticals licensing. Past and present attorneys from the US Food and Drug Administration (FDA), the EMA, and Health Sciences Agency Singapore (HSA) found that existing statutes provided authority for adaptive licensing (AL). By contrast, an attorney from Health Canada identified gaps in authority. Reimbursement during initial phases of adaptive approaches to licensing was deemed consistent with existing statutes in all jurisdictions.

Adaptive licensing: taking the next step in the evolution of drug approval.

Traditional drug licensing approaches are based on binary decisions. At the moment of licensing, an experimental therapy is presumptively transformed into a fully vetted, safe, efficacious therapy. By contrast, adaptive licensing (AL) approaches are based on stepwise learning under conditions of acknowledged uncertainty, with iterative phases of data gathering and regulatory evaluation. This approach allows approval to align more closely with patient needs for timely access to new technologies and for data to inform medical decisions. The concept of AL embraces a range of perspectives. Some see AL as an evolutionary step, extending elements that are now in place. Others envision a transformative framework that may require legislative action before implementation. This article summarizes recent AL proposals; discusses how proposals might be translated into practice, with illustrations in different therapeutic areas; and identifies unresolved issues to inform decisions on the design and implementation of AL.

Effectiveness of different footbath solutions in the treatment of digital dermatitis in dairy cows.

Three experiments were conducted to test the effectiveness of different footbath solutions and regimens in the treatment of digital dermatitis (DD) in dairy cows. During the study, groups of cows walked through allocated footbath solutions after milking on 4 consecutive occasions. All cows were scored weekly for DD lesion stage on the hind feet during milking. A "transition grade" was assigned on the basis of whether the DD lesions improved (1) or deteriorated or did not improve (0) from week to week. This grade per cow was averaged for all cows in the group. In experiment 1, 118 cows were allocated to 1 of 3 footbath treatments for 5 wk: (1) 5% CuSO(4) each week, (2) 2% ClO(-) each week, or (3) no footbath (control). The mean transition grade, and proportion of cows without DD lesions at the end of the trial were significantly higher for treatment 1 above (0.36, 0.13, and 0.11, respectively; standard error of the difference, SED = 0.057). In experiment 2, 117 cows were allocated to 1 of 4 footbath treatment regimens for 8 wk: (1) 5% CuSO(4) each week, (2) 2% CuSO(4) each week, (3) 5% CuSO(4) each fortnight, or (4) 2% CuSO(4) each fortnight. For welfare reasons, cows allocated to the weekly and fortnightly footbath regimens had an average prevalence of >60% and ≤25% active DD at the start of the trial, respectively. Significantly more cows had no DD lesions (0.53 vs. 0.36, respectively; SED = 0.049), and the mean transition grade of DD lesions was higher in the 5% compared with the 2% weekly CuSO(4) treatment (0.52 vs. 0.38, respectively; SED = 0.066). Similarly, significantly more cows had no DD lesions in the 5% compared with the 2% fortnightly CuSO(4) treatments (0.64 vs. 0.47, respectively; SED = 0.049). In experiment 3, 95 cows were allocated to 1 of 3 footbath treatments: (1) each week alternating 5% CuSO(4) with 10% salt water, (2) each week alternating 5% CuSO(4) with water, or (3) 5% CuSO(4) each fortnight (control). After 10 wk, more cows had no DD in the salt water treatment than in the control treatment (0.35 vs. 0.26, respectively; SED = 0.038), but levels of active lesions were higher for this treatment than in the other 2 treatments (0.17, 0.00, and 0.13, respectively; SED = 0.029). Treatment did not affect mean transition grade of DD lesions. In conclusion, CuSO(4) was the only footbath solution that was consistently effective for treatment of DD. In cases when DD prevalence was high, a footbath each week using 5% CuSO(4) was the most effective treatment.

Short communication: risk of severe heel erosion increased with parity and stage of lactation in freestall-housed dairy cows.

Heel erosion is the most prevalent hoof lesion in housed dairy herds, particularly in freestall facilities. It is associated with hoof contact with manure slurry and abrasive floors. The objective was to assess changes in the risk of heel erosion from the dry period to mid lactation in primiparous and multiparous dairy cows. Nineteen pregnant primiparous cows, 22 late-lactation multiparous cows (parity=3.2+/-1.4; days in milk=221+/-38), and 16 nonlactating, pregnant multiparous cows (parity=3.7+/-1.4) housed in a freestall barn with concrete flooring were followed until mid lactation. The hind hooves of all the cows were examined approximately every 7 wk and heel erosion was scored. Multiparous cows more likely had heel erosion than primiparous cows (odds ratio=11.0; 95% confidence interval=3.7, 32.7). Time relative to calving showed a significant quadratic effect, revealing that the risk of heel erosion increased more rapidly as lactation progressed. Survival analysis showed that multiparous cows had a higher relative risk of developing heel erosion than primiparous cows (hazard ratio=3.4). No cows improved between early and mid lactation, but 18 cows worsened. In conclusion, stage of lactation and parity were major risk factors for severe heel erosion in dairy cattle housed in freestalls.

Lipid content and fatty acid composition of the digital cushion of bulls offered different amounts of linseed.

Previous research suggests that the digital cushion, a shock-absorbing structure in the claw, plays an important role in protecting cattle from lameness. This study aimed to assess the degree to which nutritional factors influence the composition of the digital cushion. This involved quantifying lipid content and fatty acid composition differences in digital cushion tissue from cattle offered diets with different amounts of linseed. Forty-six bulls were allocated to 1 of 4 treatments, which were applied for an average of 140 +/- 27 d during the finishing period. The treatments consisted of a linseed supplement offered once daily on top of the basal diet (grass silage:concentrate) at 0, 400, 800, or 1,200 g of supplement/animal per day. For each treatment, the concentrate offered was adjusted to ensure that total estimated ME intake was constant across treatments. Target BW at slaughter was 540 kg. Legs were collected in 3 batches after 120, 147 and 185 d on experiment. Six samples of the digital cushion were dissected from the right lateral hind claw of each animal. Lipids were extracted and expressed as a proportion of fresh tissue, and fatty acid composition of the digital cushion was determined by gas chromatography. Data were analyzed by ANOVA, with diet, location within the digital cushion, and their interactions as fixed effects and fat content (grams per 100 g of tissue) as a covariate. Linear or quadratic contrasts were examined. The lipid content of digital cushion tissue differed between sampling locations (P < 0.001) but did not vary by treatment. There were quadratic responses to increasing linseed supplementation for several fatty acids. Although the overall proportion of C18:3n-3 (the most abundant fatty acid in linseed) did not differ (P < 0.33) by treatment, there was a quadratic influence of diet on total PUFA concentration (P = 0.003) and a linear increase in C18:3n-3 as a proportion of total PUFA (P = 0.01) in the digital cushion. This work demonstrates that dietary fatty acid composition influences the concentration of fatty acids incorporated in the digital cushion of cattle. Based on the large number of quadratic responses among the fatty acids, it appears there is a threshold amount of fatty acid incorporation in the digital cushion.

Effects of breed and production system on lameness parameters in dairy cattle.

The aim of the present study was to assess the effects of Holstein-Friesian (HF) and Norwegian (N) dairy cattle genotypes on lameness parameters in dairy cattle within different production systems over the first 2 lactations. Following calving, HF (n = 39) and N (n = 45) heifers were allocated to 1 of 3 systems of production (high level of concentrate, low level of concentrate, and grass-based). High- and low-concentrate animals were continuously housed indoors on a rotational system so that they spent similar amounts of time on slatted and solid concrete floors. Animals on the grass treatment grazed from spring to autumn in both years of the study, so that most animals on this treatment grazed from around peak to late lactation. Claw health was recorded in both hind claws of each animal at 4 observation periods during each lactation as follows: 1) -8 to 70 d postcalving, 2) 71 to 150 d postcalving, 3) 151 to 225 d postcalving, and 4) 226 to 364 d postcalving. Sole lesions, heel erosion, axial wall deviation, sole length of the right lateral hind claw (claw length), right heel width, and right lateral hind heel height were recorded as well as the presence of digital dermatitis. The N cows had lower (better) white line and total lesion scores than HF cows. Cows on the high- and low-concentrate treatments had better sole and total lesion scores than cows on the grass treatment. The HF cows had better locomotion scores than N cows. Breed and production system differences were observed with respect to claw conformation, including claw length, heel width, and heel height. Digital dermatitis was associated with worse sole lesion scores and interacted with production system to influence white line lesion scores and maximum heel erosion scores. This study shows that genetic, environmental, and infectious factors are associated with hoof pathologies in dairy cows.

Orthogonally-oriented nanotube arrays: experiment I.

Recently a new type of self-assembling surface has been proposed that, in theory, possesses a number of desirable tribological, electrical, and thermal characterstics. The surface consists of arrays of carbon nanotubes partially embedded lengthwise in a substrate such that when two arrayed surfaces are brought together orthogonally, the areal contact between them is small, limited to a lattice of nearly point-like contacts. These orthogonally-oriented nanotube arrays (ONAs) are predicted to exhibit: (i) surface adhesion (stiction) 10-100 times less than for Teflon or other advanced perfluorocarbons; (ii) frictional coefficients up to 1000 times less than for conventional solids; (iii) ultra-low wear; and (iv) superior thermal and electrical conductivity. In this paper, laboratory methods are described for embedding nanotubes in trenched substrates. Using microscopically trenched substrates and a custom ultrasonic atomization source, experiments show that individual nanotubes can spontaneously and controllably entrench themselves via interfacial forces (capillary and surface tension). Results indicate ONAs might be relatively simply and inexpensively fabricated. More decisive experiments are proposed.

Radiation induced angiosarcoma a sequela of radiotherapy for breast cancer following conservative surgery.

Radiation induced angiosarcomas (RIA) can affect breast cancer patients who had radiotherapy following conservative breast surgery. They are very rare tumors and often their diagnosis is delayed due to their benign appearance and difficulty in differentiation from radiation induced skin changes. Therefore it is very important that clinicians are aware of their existence. We report here a case of RIA followed by discussion and review of literature.

Preparation for professional self-regulation.

This article asserts that graduate study should include preparation for participation in the process of self-regulation to assure the responsible conduct of research in the scientific community. This article outlines the various ways in which doctoral study can incorporate such preparation. These suggested ways include the inculcation of general attitudes and values about professional self-regulation, various ways doctoral study can be configured so that future scientists are prepared to participate in the deterrence, detection and sanctioning of scientific wrongdoing. The stages of doctoral study in the United States and their relevance to preparation for self-regulations are also discussed. Recommendations regarding an extended role for faculty advisors, graduate assistantships, coursework and departmental policies and activities are also advanced.

Using localizing learning to improve supervised learning algorithms.

Slow learning of neural-network function approximators can frequently be attributed to interference, which occurs when learning in one area of the input space causes unlearning in another area. To mitigate the effect of unlearning, this paper develops an algorithm that adjusts the weights of an arbitrary, nonlinearly parameterized network such that the potential for future interference during learning is reduced. This is accomplished by the reduction of a biobjective cost function that combines the approximation error and a term that measures interference. An analysis of the algorithm's convergence properties shows that learning with this algorithm reduces future unlearning. The algorithm can be used either during online learning or can be used to condition a network to have immunity from interference during a future learning stage. A simple example demonstrates how interference manifests itself in a network and how less interference can lead to more efficient learning. Simulations demonstrate how this new learning algorithm speeds up the training in various situations due to the extra cost function term.

Protecting TPN and lipid infusions from light: reducing hydroperoxides in NICU patients.

The use of total parenteral nutrition (TPN) and intravenous fat emulsions in sick or preterm infants is often required to maintain adequate nutrition, yet recent research has shown that when exposed to light these nutrients are altered and deliver a high load of exogenous toxic hydroperoxides to already compromised infants. Hydroperoxides cause damage at the cellular level unless mediated by the body's antioxidant systems. NICU patients are, by definition, patients at risk. Preterm infants have low antioxidant reserves and, like sick term infants, typically suffer significant oxidative stress. Endogenous hydroperoxides alone may overwhelm defenses. The addition of hyperperoxides from light-exposed TPN or fat emulsions increases the risk of tissue damage. Hydroperoxides have been associated with hypoxic-ischemic encephalopathy, intraventricular hemorrhage, periventricular leukomalacia, chronic lung disease, retinopathy of prematurity, and necrotizing enterocolitis. By protecting these infusates from light, bedside nurses can reduce the amount of hydroperoxides infused and protect NICU patients from the associated risks.

Influence of storage upon light-induced chlorogenic acid accumulation in potato tubers (Solanum tuberosum L.).

The influence of 2 weeks and 3 months of dark storage upon light-induced chlorogenic acid accumulation within tuber tissue of four potato cultivars and upon 5-, 4-, and 3-caffeoylquinic acid concentrations within cv. King Edward was determined. Storage period significantly affected (P < 0.05) the magnitude of the light-induced chlorogenic acid response with accumulation rates 3-4 times higher in tubers exposed to light after 2 weeks compared with those placed under light after 3 months. Comparison of chlorogenic acid concentrations in controls after 2 and 3 months of dark storage indicated that tuber chlorogenic concentrations decline during prolonged cold store at 5 degrees C. Rates of accumulation in response to light were cultivar-dependent with cv. Fianna the most light-sensitive and cv. Maris Piper relatively light-insensitive. In virtually all cases exposure to sodium and fluorescent light promoted higher rates of accumulation than did exposure to high-pressure mercury light sources. Chlorogenic acid values steadily increased over 15 days of illumination with, in the majority of cases, no indication of cessation. Light exposure increased 5-, 4-, and 3-caffeoylquinic acid accumulation rates in cv. King Edward. Irrespective of storage period and light source, ratios of 5-:4-:3-caffeoylquinic acid were ca. 85:15:0 at day 0 and 52:42:6 by day 15.

Delineation of the critical interval of Bardet-Biedl syndrome 1 (BBS1) to a small region of 11q13, through linkage and haplotype analysis of 91 pedigrees.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous recessive disease characterized primarily by atypical retinitis pigmentosa, obesity, polydactyly, hypogenitalism, and mental retardation. Despite the presence of at least five loci in the human genome, on chromosomes 2q, 3p, 11q, 15q and 16q, as many as 50% of the mutations appear to map to the BBS1 locus on 11q13. The recessive mode of inheritance and the genetic heterogeneity of the syndrome, as well as the inability to distinguish between different genetic loci by phenotypic analyses, have hindered efforts to delineate the 11q13 region as a first step toward cloning the mutated gene. To circumvent these difficulties, we collected a large number of BBS pedigrees of primarily North American and European origin and performed genetic analysis, using microsatellites from all known BBS genomic regions. Heterogeneity analysis established a 40.5% contribution of the 11q13 locus to BBS, and haplotype construction on 11q-linked pedigrees revealed several informative recombinants, defining the BBS1 critical interval between D11S4205 and D11S913, a genetic distance of 2.9 cM, equivalent to approximately 2.6 Mb. Loss of identity by descent in two consanguineous pedigrees was also observed in the region, potentially refining the region to 1.8 Mb between D11S1883 and D11S4944. The identification of multiple recombinants at the same position forms the basis for physical mapping efforts, coupled with mutation analysis of candidate genes, to identify the gene for BBS1.

Dose-dependent hyperlipidemia in rabbits following administration of poloxamer 407 gel.

Poloxamer 407 (P-407) is a tri-block polymer that exhibits concentration-dependent reverse thermal gelation, a characteristic potentially useful for developing sustained release injectable drugs. While some reports suggest that P-407 is 'non-toxic', rodent studies demonstrate that P-407 induces hyperlipidemia, an action that makes this polymer a questionable drug delivery vehicle. Unfortunately, the majority of earlier studies employed supra-physiologic doses of P-407. The present study examined if lower, clinically useful, doses of gel-forming concentrations of P-407 induced hyperlipidemia in rabbits. Male and female rabbits were injected with 5.5 mg/kg (0.025 mL/kg), 27.5 mg/kg (0.125 mL/kg), or 137.5 mg/kg (0.625 mL/kg) of 22% P-407 and the actions of this polymer on blood chemistry were assessed at 6 h, 1 d, 2 d, 7 d, and 14 d following injection. Control rabbits received no injection. The highest dose of P-407 (137.5 mg/kg) significantly increased serum triglycerides and cholesterol in both male and female rabbits with the maximum increase observed at 2 d after injection. Male rabbits were more sensitive to P-407 than females following injection of 137.5 mg/kg P-407. The lower doses of P-407 did not alter serum triglycerides or cholesterol. In all groups, serum triglycerides and cholesterol were at baseline levels by 14 d. P-407 did not affect other blood chemistry parameters. Although P-407 induces a dose-dependent hyperlipidemia in rabbits, low doses of this polymer may be used in controlled release drug delivery applications without the untoward hyperlipidemic effect.

Stress-induced legume root nodule senescence. Physiological, biochemical, and structural alterations.

Nitrate-fed and dark-stressed bean (Phaseolus vulgaris) and pea (Pisum sativum) plants were used to study nodule senescence. In bean, 1 d of nitrate treatment caused a partially reversible decline in nitrogenase activity and an increase in O(2) diffusion resistance, but minimal changes in carbon metabolites, antioxidants, and other biochemical parameters, indicating that the initial decrease in nitrogenase activity was due to O(2) limitation. In pea, 1 d of dark treatment led to a 96% decline in nitrogenase activity and sucrose, indicating sugar deprivation as the primary cause of activity loss. In later stages of senescence (4 d of nitrate or 2-4 d of dark treatment), nodules showed accumulation of oxidized proteins and general ultrastructural deterioration. The major thiol tripeptides of untreated nodules were homoglutathione (72%) in bean and glutathione (89%) in pea. These predominant thiols declined by approximately 93% after 4 d of nitrate or dark treatment, but the loss of thiol content can be only ascribed in part to limited synthesis by gamma-glutamylcysteinyl, homoglutathione, and glutathione synthetases. Ascorbate peroxidase was immunolocalized primarily in the infected and parenchyma (inner cortex) nodule cells, with large decreases in senescent tissue. Ferritin was almost undetectable in untreated bean nodules, but accumulated in the plastids and amyloplasts of uninfected interstitial and parenchyma cells following 2 or 4 d of nitrate treatment, probably as a response to oxidative stress.