Swallowing dysfunctions in patients with disorders of consciousness: Evidence from neuroimaging data, assessment, and management.

Following severe brain injuries, a subset of patients may remain in an altered state of consciousness; most of these patients require artificial feeding. Currently, a functional oral phase and the presence of exclusive oral feeding may constitute signs of consciousness. Additionally, the presence of pharyngo-laryngeal secretions, saliva aspiration, cough reflex and tracheostomy are related to the level of consciousness. However, the link between swallowing and consciousness is yet to be fully understood. The primary aim of this review is to establish a comprehensive overview of the relationship between an individual's conscious behaviour and swallowing (reflexive and voluntary). Previous studies of brain activation during volitional and non-volitional swallowing tasks in healthy subjects are also reviewed. We demonstrate that the areas activated by voluntary swallowing tasks (primary sensorimotor, cingulate, insula, premotor, supplementary motor, cerebellum, and operculum) are not specific to deglutitive function but are shared with other motor tasks and brain networks involved in consciousness. This review also outlines suitable assessment and treatment methods for dysphagic patients with disorders of consciousness. Finally, we propose that markers of swallowing could contribute to the development of novel diagnostic guidelines for patients with disorders of consciousness.

Assessment of p.Phe508del-CFTR functional restoration in pediatric primary cystic fibrosis airway epithelial cells.

BACKGROUND: Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene can reduce function of the CFTR ion channel activity and impair cellular chloride secretion. The gold standard method to assess CFTR function of ion transport using the Ussing chamber requires a high number of airway epithelial cells grown at air-liquid interface, limiting the application of this method for high throughput screening of potential therapeutic compounds in primary airway epithelial cells (pAECs) featuring less common CFTR mutations. This study assessed an alternative approach, using a small scale halide assay that can be adapted for a personalized high throughput setting to analyze CFTR function of pAEC. METHODS: Pediatric pAECs derived from children with CF (pAECCF) were established and expanded as monolayer cultures, before seeding into 96-well plates for the halide assay. Cells were then transduced with an adenoviral construct containing yellow fluorescent protein (eYFP) reporter gene, alone or in combination with either wild-type CFTR (WT-CFTR) or p.Phe508del CFTR. Four days post transduction, cells were stimulated with forskolin and genistein, and assessed for quenching of the eYFP signal following injection of iodide solution into the assay media. RESULTS: Data showed that pAECCF can express eYFP at high efficiency following transduction with the eYFP construct. The halide assay was able to discriminate functional restoration of CFTR in pAECCF treated with either WT-CFTR construct or the positive controls syntaxin 8 and B-cell receptor-associated protein 31 shRNAs. SIGNIFICANCE: The current study demonstrates that the halide assay can be adapted for pediatric pAECCF to evaluate restoration of CFTR function. With the ongoing development of small molecules to modulate the folding and/or activity of various mutated CFTR proteins, this halide assay presents a small-scale personalized screening platform that could assess therapeutic potential of molecules across a broad range of CFTR mutations.

Initial recommendations for higher-tier risk assessment protocols for bumble bees, Bombus spp. (Hymenoptera: Apidae).

Global declines of bumble bees and other pollinator populations are of concern because of their critical role for crop production and maintenance of wild plant biodiversity. Although the consensus among scientists is that the interaction of many factors, including habitat loss, forage scarcity, diseases, parasites, and pesticides, potentially plays a role in causing these declines, pesticides have received considerable attention and scrutiny. In response, regulatory agencies have introduced more stringent pollinator testing requirements for registration and reregistration of pesticides, to ensure that the risks to pollinators are minimized. In this context, guidelines for testing bumble bees (Bombus spp.) in regulatory studies are not yet available, and a pressing need exists to develop suitable protocols for routine higher-tier studies with these non-Apis sp., social bees. To meet this need, Bayer CropScience LP, Syngenta Crop Protection LLC US, and Valent USA. Corporation organized a workshop bringing together a group of global experts on bumble bee behavior, ecology, and ecotoxicology to discuss and develop draft protocols for both semi-field (Tier II) and field (Tier III) studies. The workshop was held May 8-9, 2014, at the Bayer Bee Care Center, North Carolina, USA. The participants represented academic, consulting, and industry scientists from Europe, Canada, the United States, and Brazil. The workshop identified a clear protection goal and generated proposals for basic experimental designs, relevant measurements, and endpoints for both semifield (tunnel) and field tests. These initial recommendations are intended to form the basis of discussions to help advance the development of appropriate protocol guidelines.

Impact of bariatric surgery on life expectancy in severely obese patients with diabetes: a decision analysis.

OBJECTIVE: To create a decision analytic model to estimate the balance between treatment risks and benefits for severely obese patients with diabetes. BACKGROUND: Bariatric surgery leads to many desirable metabolic changes, but long-term impact of bariatric surgery on life expectancy in patients with diabetes has not yet been quantified. METHODS: We developed a Markov state transition model with multiple Cox proportional hazards models and logistic regression models as inputs to compare bariatric surgery versus no surgical treatment for severely obese diabetic patients. The model is informed by data from 3 large cohorts: (1) 159,000 severely obese diabetic patients (4185 had bariatric surgery) from 3 HMO Research Network sites; (2) 23,000 subjects from the Nationwide Inpatient Sample; and (3) 18,000 subjects from the National Health Interview Survey linked to the National Death Index. RESULTS: In our main analyses, we found that a 45-year-old woman with diabetes and a body mass index (BMI) of 45 kg/m gained an additional 6.7 years of life expectancy with bariatric surgery (38.4 years with surgery vs 31.7 years without surgery). Sensitivity analyses revealed that the gain in life expectancy decreased with increasing BMI, until a BMI of 62 kg/m is reached, at which point nonsurgical treatment was associated with greater life expectancy. Similar results were seen for both men and women in all age groups. CONCLUSIONS: For most severely obese patients with diabetes, bariatric surgery seems to improve life expectancy; however, surgery may reduce life expectancy for the super obese with BMIs over 62 kg/m.

Therapeutic assessment of SEED: a new engineered antibody platform designed to generate mono- and bispecific antibodies.

The strand-exchange engineered domain (SEED) platform was designed to generate asymmetric and bispecific antibody-like molecules, a capability that expands therapeutic applications of natural antibodies. This new protein engineered platform is based on exchanging structurally related sequences of immunoglobulin within the conserved CH3 domains. Alternating sequences from human IgA and IgG in the SEED CH3 domains generate two asymmetric but complementary domains, designated AG and GA. The SEED design allows efficient generation of AG/GA heterodimers, while disfavoring homodimerization of AG and GA SEED CH3 domains. Using a clinically validated antibody (C225), we tested whether Fab derivatives constructed on the SEED platform retain desirable therapeutic antibody features such as in vitro and in vivo stability, favorable pharmacokinetics, ligand binding and effector functions including antibody-dependent cell-mediated cytotoxicity and complement-dependent cytotoxicity. In addition, we tested SEED with combinations of binder domains (scFv, VHH, Fab). Mono- and bivalent Fab-SEED fusions retain full binding affinity, have excellent biochemical and biophysical stability, and retain desirable antibody-like characteristics conferred by Fc domains. Furthermore, SEED is compatible with different combinations of Fab, scFv and VHH domains. Our assessment shows that the new SEED platform expands therapeutic applications of natural antibodies by generating heterodimeric Fc-analog proteins.

Refined avian risk assessment for aldicarb in the United States.

Aldicarb was recently reviewed by the US Environmental Protection Agency (USEPA) for re-registration eligibility. In this paper, we describe a refined avian risk assessment for aldicarb that was conducted to build upon the screening-level methods used by USEPA. The goal of the refined ERA was to characterize and understand better the risks posed by aldicarb to birds in areas where the pesticide is applied. Aldicarb is a systemic insecticide sold in granular form under the trade name Temik. It is applied directly to soil and is used to control mites, nematodes, and aphids on a variety of crops (e.g., cotton, potatoes, peanuts). Consumption of grit is necessary for proper digestion in many bird species, particularly for granivores and insectivores. Thus, aldicarb granules may be mistaken for grit by birds. The Granular Pesticide Avian Risk Assessment Model (GranPARAM) is described in a companion paper and was used to estimate the probability and magnitude of effects to flocks of birds that frequent aldicarb-treated fields. One hundred thirty-five exposure scenarios were modeled that together include a range of bird species, crops, application methods and rates, and regions in the United States. The results indicated that, even for the most sensitive bird species, the risks associated with the agricultural use of granular aldicarb are negligible to low. There are several reasons for the limited risk: 1) the Temik formulation includes a gypsum core and a graphite coating and is black in color, all of which have been shown to be unattractive to birds, and 2) the pesticide is applied subsurface and rapidly dissolves following contact with water. The fact that no bird kill incidents involving appropriate label uses of aldicarb have been conclusively documented in the United States over its 38 years of use supports the results of this refined risk assessment.

Refined aquatic risk assessment for aldicarb in the United States.

Aldicarb is a systemic insecticide applied directly to soil and to control mites, nematodes, and aphids on a variety of crops (e.g., cotton, potatoes, peanuts). It is highly soluble in water (6,000 mg/L) and mobile in soils (K(oc) = 100). As a result, aldicarb has the potential to be transported to aquatic systems close to treated fields. The US Environmental Protection Agency (USEPA) recently conducted an aquatic screening-level ERA for aldicarb as part of the re-registration review process. We conducted a refined risk assessment for aldicarb to characterize better the risks posed by aldicarb to fish and invertebrates inhabiting small freshwater ponds near agricultural areas. For the exposure assessment, tier II PRZM/EXAMS (Predicted Root Zone Model [PRZM] and Exposure Analysis Modelling System [EXAMS]) modelling was conducted to estimate 30-y distributions of peak concentrations of aldicarb and the carbamate metabolites (aldicarb sulfoxide, aldicarb sulfone) in surface waters of a standard pond arising from different uses of aldicarb. The effects assessment was performed using a species sensitivity distribution (SSD) approach. The resulting risk curves as well as available incident reports suggest that risks to freshwater fish and invertebrates from exposure to aldicarb are minor. The available monitoring data did not provide conclusive evidence about risks to aquatic biota.

Probabilistic risk-assessment model for birds exposed to granular pesticides.

For granular formulations of pesticides, direct consumption by birds is generally the most important route of exposure. A probabilistic exposure model was developed that estimates how many pesticide granules a bird ingests and, from that, the quantity of pesticide ingested. This model, referred to as the "granular pesticide avian risk assessment model" (GranPARAM), has input variables not included in current screening-level assessments for granular pesticides, such as proportion of time for which birds forage in the field, grit ingestion rates, attractiveness of pesticide granules compared with natural grit, and proportions of soil particles and pesticide granules in the size range consumed by birds. For input variables that are uncertain, variable, or both, distributions are used rather than point estimates. Monte Carlo analysis is then performed to propagate input variable uncertainties through the exposure model for granular pesticides. The outputs from the exposure portion of GranPARAM are estimated pesticide doses for each of 20 birds of a selected species on each of 1000 fields. The dose for each bird is compared with a randomly chosen dose from the dose-response curve for that species or an appropriate surrogate. If the exposure dose for a bird exceeds the randomly chosen effects dose, the bird is considered dead; otherwise, the bird is assumed to be alive. Thus, the risk output from GranPARAM is a bar chart showing the percentages of fields with 0/20 dead birds, 1/20 dead birds, 2/20 dead birds, and so forth.

Decision modeling to estimate the impact of gastric bypass surgery on life expectancy for the treatment of morbid obesity.

OBJECTIVE: To create a decision analytic model to estimate the balance between treatment risks and benefits for patients with morbid obesity. DESIGN: Decision analytic Markov state transition model with multiple logistic regression models as inputs. Data from the 2005 National Inpatient Survey were used to calculate in-hospital mortality risk associated with bariatric surgery and then adjusted for 30-day mortality. To calculate excess mortality associated with obesity, we used the 1991-1996 National Health Interview Survey linked to the National Death Index. Bariatric surgery was assumed to influence mortality only through its impact on the excess mortality associated with obesity, and the efficacy of surgery was estimated from a recent large observational trial. INTERVENTION: Gastric bypass surgery. Main Outcome Measure Life expectancy. RESULTS: Our base case, a 42-year-old woman with a body mass index of 45, gained an additional 2.95 years of life expectancy with bariatric surgery. No surgical treatment was favored in our base case when the 30-day surgical mortality exceeded 9.5% (baseline 30-day mortality, 0.2%) or when the efficacy of bariatric surgery for reducing mortality decreased to 2% or less (baseline efficacy, 53%). CONCLUSIONS: The optimal decision for individual patients varies based on the balance of risk between perioperative mortality, excess annual mortality risk associated with increasing body mass index, and the efficacy of surgery; however, for the average morbidly obese patient, gastric bypass improves life expectancy.

Monte Carlo Green's function formalism for the propagation of partially coherent light.

We present a Monte Carlo-derived Green's function for the propagation of partially spatially coherent fields. This Green's function, which is derived by sampling Huygens-Fresnel wavelets, can be used to propagate fields through an optical system and to compute first- and second-order field statistics directly. The concept is illustrated for a cylindrical f/1 imaging system. A Gaussian copula is used to synthesize realizations of a Gaussian Schell-model field in the pupil plane. Physical optics and Monte Carlo predictions are made for the first- and second-order statistics of the field in the vicinity of the focal plane for a variety of source coherence conditions. Excellent agreement between the physical optics and Monte Carlo predictions is demonstrated in all cases. This formalism can be generally employed to treat the interaction of partially coherent fields with diffracting structures.

Monte Carlo modeling of spatial coherence: free-space diffraction.

We present a Monte Carlo method for propagating partially coherent fields through complex deterministic optical systems. A Gaussian copula is used to synthesize a random source with an arbitrary spatial coherence function. Physical optics and Monte Carlo predictions of the first- and second-order statistics of the field are shown for coherent and partially coherent sources for free-space propagation, imaging using a binary Fresnel zone plate, and propagation through a limiting aperture. Excellent agreement between the physical optics and Monte Carlo predictions is demonstrated in all cases. Convergence criteria are presented for judging the quality of the Monte Carlo predictions.

Accounting for differing exposure patterns between laboratory tests and the field in the assessment of long-term risks of pesticides to terrestrial vertebrates.

Long-term risks of pesticides to birds and mammals are currently assessed by comparing effects thresholds determined in chronic laboratory studies to exposure levels expected to occur in the field. However, there is often a mismatch between exposure patterns tested in the laboratory tests (exposure levels held constant) and those experienced by animals in the field (exposure levels varying over time). Three methods for addressing this problem are presented and discussed. Time-weighted averaging (TWA) converts a variable field exposure regime to a single value that can be compared directly to the laboratory test results. Body-burden modeling (BBM) is applied to both laboratory and field exposure regimes allowing a straightforward comparison of body residue levels expected for each situation. Temporal analysis (TA) uses expert judgment to decide if the length of time exposure exceeds a toxicity threshold is long enough to cause biologically significant effects. To reduce uncertainty in long-term assessments, the conduct of specialized laboratory tests in which test subjects are administered a time-varying exposure that mimics what occurs in the field should be considered. Such tests may also be useful testing the validity of each of these assessment methods.

Apoptosis in proliferative vitreoretinopathy.

PURPOSE: To study the involvement of apoptosis using different apoptosis markers in PVR pathogenesis. METHODS: The presence of mRNA coding for Fas, Fas ligand (FasL), and TNF-related apoptosis inducing ligand (TRAIL) was investigated in vitreous samples from 46 consecutive patients-25 with PVR, 11 with retinal detachment (RD) not complicated by PVR, and 10 with macular hole (MH)-using RT-PCR. From previously examined vitreous samples, 21 PVR, 9 RD, and 10 MH were examined for their levels of TGF-beta2 protein with sandwich ELISA kits. Five epiretinal membranes excised from five patients with PVR were also examined for apoptotic cell death using the terminal deoxytransferase (TdT) mediated dUTP-biotin nick end labeling (TUNEL) technique. RESULTS: FAS mRNA was detected in 72% of patients with PVR, 55% of patients with RD and 20% of patients with MH. TRAIL mRNA was detected in 67% of patients with PVR, 89% of patients with RD, and 20% of patients with MH. FasL mRNA was detected in 20% of patients with PVR, 9% of patients with RD, and 10% of patients with MH. The median levels of Fas and TRAIL mRNA were significantly higher (P < 0.05) in patients with PVR than in those with MH hole but between patients with PVR and those with RD the difference was not significant (P > 0.05). A significant difference was detected between RD and MH for TRAIL mRNA levels (P = 0.008). For FasL, no significant difference between groups was found. TGF-beta2 was detected in all investigated vitreous samples. A significant difference was found between the PVR and MH groups (P = 0.001) and between the RD and MH groups (P = 0.004), but not between the PVR and RD groups (P < 0.05). The level of TGF-beta2 was significantly correlated to the level of TRAIL mRNA (r = 0.86), but no correlation was found between TGF-beta2 and Fas mRNA levels (r = 0.21). Four of five examined PVR epiretinal membranes showed positive staining for apoptotic cells using the TUNEL technique. CONCLUSIONS: Apoptosis is one of the mechanisms that is involved in PVR pathogenesis. Different apoptosis markers suggest different pathways occur in PVR, including Fas/FasL, TRAIL, and TGF-beta2 mediated processes.

Bilateral anterior cruciate ligament reconstruction as a single procedure: evaluation of cost and early functional results.

BACKGROUND: The ideal treatment for patients presenting with bilateral anterior cruciate ligament (ACL) deficiency remains controversial. PURPOSE: To evaluate cost and early functional results after bilateral ACL reconstruction at a single setting. STUDY DESIGN: Retrospective review. METHODS: Eleven patients (22 knees) who underwent bilateral ACL reconstruction at a single setting were compared with 33 patients (35 knees) who underwent unilateral ACL reconstruction during the same time period. RESULTS: The mean time to full unrestricted activity between groups was 6.5 months for both groups (P = 0.92). There were no significant differences between groups at latest follow-up for complication rates or laxity as judged by Lachman test, pivot shift test, and KT 1000 arthrometry. The mean International Knee Documentation Committee subjective score at a mean 3.1-year follow-up was 91.9 for the bilateral ACL group compared to 92.0 for the unilateral ACL group (P = 0.95). There was a total cost savings per knee (based on 2001 dollars) of $3751.59 when performing bilateral ACL reconstruction at a single setting (P = 0.0001). CONCLUSIONS: For patients presenting with bilateral ACL deficient knees, reconstruction of both knees at a single setting is safe, cost effective, and does not appear to compromise early functional results.