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Background: Despite advancements in the successful use of immunotherapy in treating a variety of solid tumors, applications in treating brain tumors have lagged considerably. This is due, at least in part, to the lack of well-characterized antigens expressed within brain tumors that can mediate tumor rejection; the low mutational burden of these tumors that limits the abundance of targetable neoantigens; and the immunologically "cold" tumor microenvironment that hampers the generation of sustained and productive immunologic responses. The field of mRNA-based therapeutics has experienced a boon following the universal approval of COVID-19 mRNA vaccines. mRNA-based immunotherapeutics have also garnered widespread interest for their potential to revolutionize cancer treatment. In this study, we developed a novel and scalable approach for the production of personalized mRNA-based therapeutics that target multiple tumor rejection antigens in a single therapy for the treatment of refractory brain tumors., Methods: Tumor-specific neoantigens and aberrantly overexpressed tumor-associated antigens were identified for glioblastoma and medulloblastoma tumors using our cancer immunogenomics pipeline called Open Reading Frame Antigen Network (O.R.A.N). Personalized tumor antigen-specific mRNA vaccine was developed for each individual tumor model using selective gene capture and enrichment strategy. The immunogenicity and efficacy of the personalized mRNA vaccines was evaluated in combination with anti-PD-1 immune checkpoint blockade therapy or adoptive cellular therapy with ex vivo expanded tumor antigen-specific lymphocytes in highly aggressive murine GBM models., Results: Our results demonstrate the effectiveness of the antigen-specific mRNA vaccines in eliciting robust anti-tumor immune responses in GBM hosts. Our findings substantiate an increase in tumor-infiltrating lymphocytes characterized by enhanced effector function, both intratumorally and systemically, after antigen-specific mRNA-directed immunotherapy, resulting in a favorable shift in the tumor microenvironment from immunologically cold to hot. Capacity to generate personalized mRNA vaccines targeting human GBM antigens was also demonstrated., Conclusions: We have established a personalized and customizable mRNA-therapeutic approach that effectively targets a plurality of tumor antigens and demonstrated potent anti-tumor response in preclinical brain tumor models. This platform mRNA technology uniquely addresses the challenge of tumor heterogeneity and low antigen burden, two key deficiencies in targeting the classically immunotherapy-resistant CNS malignancies, and possibly other cold tumor types., (© 2024. The Author(s).)

The list of EPA-approved disinfectants for coronavirus features many products for use on hard, non-porous materials. There are significantly fewer products registered for use on porous materials. Further, many common, high-touch surfaces fall in between non-porous materials such as glass and porous materials such as soft fabrics. The objective of this study was to assess the efficacy of selected commercially available disinfectant products against coronaviruses on common, high-touch surfaces. Four disinfectants (Clorox Total 360, Bleach solution, Vital Oxide, and Peroxide Multi-Surface Cleaner) were evaluated against Murine Hepatitis Virus A59 (MHV) as a surrogate coronavirus for SARS-CoV-2. MHV in cell culture medium was inoculated onto four materials: stainless steel, latex-painted drywall tape, Styrene Butadiene rubber (rubber), and bus seat fabric. Immediately (T0) or 2-hr (T2) post-inoculation, disinfectants were applied by trigger-pull or electrostatic sprayer and either held for recommended contact times (Spray only) or immediately wiped (Spray and Wipe). Recovered infectious MHV was quantified by median tissue culture infectious dose assay. Bleach solution, Clorox Total 360, and Vital Oxide were all effective (>3-log 10 reduction or complete kill of infectious virus) with both the Spray Only and Spray and Wipe methods on stainless steel, rubber, and painted drywall tape when used at recommended contact times at both T0 and T2 hr. Multi-Surface Cleaner unexpectedly showed limited efficacy against MHV on stainless steel within the recommended contact time; however, it showed increased (2.3 times greater efficacy) when used in the Spray and Wipe method compared to Spray Only. The only products to achieve a 3-log 10 reduction on fabric were Vital Oxide and Clorox Total 360; however, the efficacy of Vital Oxide against MHV on fabric was reduced to below 3-log 10 when applied by an electrostatic sprayer compared to a trigger-pull sprayer. This study highlights the importance of considering the material, product, and application method when developing a disinfection strategy for coronaviruses on high-touch surfaces.

Introduction: There has been little research to explore how adults financially value private orthodontic treatment and whether they have preferences for different attributes of treatment. This study used a discrete choice experiment and aimed to determine whether the recognized skill level of the dental professional and the type of orthodontic appliance influence the values that the public places on private adult orthodontic treatment., Methods: In total, 206 adult patients or the parents/guardians of children attending general dental practices in the northeast of England were recruited to complete a discrete choice experiment. Three attributes were included: the type of dental professional providing treatment, the type of orthodontic appliance, and cost. Also collected were demographic and orthodontic history characteristics. Results were analyzed with conditional logistic regression and elicited marginal willingness to pay (MWTP)., Results: Participants value the training and expertise of the dental professional providing private orthodontic treatment greater than the type of orthodontic appliance. MWTP for orthodontic treatment increased in conjunction with the recognized skill level of the dental professional. Participants were willing to pay more for aesthetic appliances over a fixed metal appliance., Conclusions: Participants value the training and expertise of the dental professional providing private adult orthodontic treatment greater than the type of orthodontic appliance. These preferences concur with other discrete choice experiments undertaken in medical specialties that included attributes focusing on the qualification, skill, or expertise of the health care professional. MWTP for orthodontic treatment increased in conjunction with the recognized skill level of the dental professional. Participants were willing to pay more for aesthetic appliances than metal fixed appliances. The cost of orthodontics is significant, and adults appreciate the importance of having options and making choices. Knowledge Transfer Statement: The results of this study suggest that patients are willing to pay more for orthodontic services provided by clinicians with higher levels of formal training. In a competitive market where the public appears to prefer the provider over treatment modality, there is an incentive for clinicians to optimize their knowledge and skills to deliver the high-quality orthodontic treatment that patients are demanding. Orthodontic clinicians should be mindful of the demand for the different adult orthodontic appliances and tailor their skill sets accordingly.

Purpose: We evaluated the impact of personal melanoma genomic risk information on sun-related behaviors and psychological outcomes., Methods: In this parallel group, open, randomized controlled trial, 1,025 Australians of European ancestry without melanoma and aged 18-69 years were recruited via the Medicare database (3% consent). Participants were randomized to the intervention (n = 513; saliva sample for genetic testing, personalized melanoma risk booklet based on a 40-variant polygenic risk score, telephone-based genetic counseling, educational booklet) or control (n = 512; educational booklet). Wrist-worn ultraviolet (UV) radiation dosimeters (10-day wear) and questionnaires were administered at baseline, 1 month postintervention, and 12 months postbaseline., Results: At 12 months, 948 (92%) participants completed dosimetry and 973 (95%) the questionnaire. For the primary outcome, there was no effect of the genomic risk intervention on objectively measured UV exposure at 12 months, irrespective of traditional risk factors. For secondary outcomes at 12 months, the intervention reduced sunburns (risk ratio: 0.72, 95% confidence interval: 0.54-0.96), and increased skin examinations among women. Melanoma-related worry was reduced. There was no overall impact on general psychological distress., Conclusion: Personalized genomic risk information did not influence sun exposure patterns but did improve some skin cancer prevention and early detection behaviors, suggesting it may be useful for precision prevention. There was no evidence of psychological harm., (© 2021. The Author(s).)

Background: There is a need for greater understanding of the spectrum of emotional and behavioural reactions that individuals in the general population may experience in response to genomic testing for melanoma risk., Objectives: To explore how individuals in the general population respond to receiving personalized genomic risk of melanoma., Methods: Semistructured interviews were undertaken with 30 participants (aged 24-69 years, 50% female, 12 low risk, eight average risk, 10 high risk) recruited from a pilot trial in which they received personalized melanoma genomic risk information. We explored participants' emotional and behavioural responses to receiving their melanoma genomic risk information. The qualitative data were analysed thematically., Results: Many participants reported a positive response to receiving their melanoma genomic risk, including feelings of happiness, reassurance and gaining new knowledge to help manage their melanoma risk. Some participants reported short-term negative emotional reactions that dissipated over time. Most individuals, particularly those who received average or high-risk results, reported making positive behaviour changes to reduce their melanoma risk. Emotional and behavioural responses were linked to participants' expectations for their risk result, their pre-existing perception of their own melanoma risk, their existing melanoma preventive behaviours and their genomic risk category., Conclusions: Personalized melanoma genomic risk information alongside education and lifestyle counselling is favourably received by people without a personal history and unselected for a family history of melanoma. Participants described increased knowledge and awareness around managing skin cancer risk and improved sun protection and skin examination behaviours. Any initial feelings of distress usually dissipated over time., (© 2018 British Association of Dermatologists.)

The aim of this research was to understand how genomics-based personal melanoma risk information impacts psychological and emotional health outcomes in the general population. In a pilot randomized controlled trial, participants (n = 103) completed the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire, 3 months after receiving personal melanoma genomic risk information. Mean scores for MICRA items and subscales were stratified by genomic risk group (low, average, high), gender, education, age, and family history of melanoma. P values were obtained from t-tests and analysis of variance tests. We found that overall, participants (mean age: 53 years, range: 21-69; 52% female) had a total MICRA mean score of 18.6 (standard deviation: 11.1, range: 1-70; possible range: 0-105). The high genomic risk group had higher mean scores for the total (24.2, F 2,100  = 6.7, P = 0.0019), distress (3.3, F 2,100  = 9.4, P = 0.0002) and uncertainty (8.5, F 2,100  = 6.5, P = 0.0021) subscales compared with average (17.6, 1.1, and 4.5, respectively) and low-risk groups (14.1, 0.5, and 2.5, respectively). Positive experiences scores were consistent across risk groups. In conclusion, MICRA scores for the total, distress and uncertainty subscales in our study were relatively low overall, but people who receive a high genomic risk result may benefit from increased support following testing.

Background: Reducing ultraviolet radiation (UV) exposure and improving early detection may reduce melanoma incidence, mortality and health system costs. This study aims to evaluate the efficacy and cost-effectiveness of providing information on personal genomic risk of melanoma in reducing UV exposure at 12 months, according to low and high traditional risk., Methods: In this randomized controlled trial, participants (target sample = 892) will be recruited from the general population, and randomized (1:1 ratio, intervention versus control). Intervention arm participants provide a saliva sample, receive personalized melanoma genomic risk information, a genetic counselor phone call, and an educational booklet on melanoma prevention. Control arm participants receive only the educational booklet. Eligible participants are aged 18-69 years, have European ancestry and no personal history of melanoma. All participants will complete a questionnaire and wear a UV dosimeter to objectively measure their sun exposure at baseline, 1- and 12-month time-points, except 1-month UV dosimetry will be limited to ~250 participants. The primary outcome is total daily Standard Erythemal Doses at 12 months. Secondary outcomes include objectively measured UV exposure for specific time periods (e.g. midday hours), self-reported sun protection and skin-examination behaviors, psycho-social outcomes, and ethical considerations surrounding offering genomic testing at a population level. A within-trial and modelled economic evaluation will be undertaken from an Australian health system perspective to assess the intervention costs and outcomes., Discussion: This trial will inform the clinical and personal utility of introducing genomic testing into the health system for melanoma prevention and early detection at a population-level., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12617000691347., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Communication of personalized melanoma genomic risk information may improve melanoma prevention behaviors., Methods: We evaluated the feasibility and acceptability of communicating personalized genomic risk of melanoma to the public and its preliminary impact on behaviors and psychosocial outcomes. One hundred eighteen people aged 22 to 69 years provided a saliva sample and were randomized to the control (nonpersonalized educational materials) or intervention (personalized booklet presenting melanoma genomic risk as absolute and relative risks and a risk category based on variants in 21 genes, telephone-based genetic counseling, and nonpersonalized educational materials). Intention-to-treat analyses overall and by-risk category were conducted using ANCOVA adjusted for baseline values., Results: Consent to participate was 41%, 99% were successfully genotyped, and 92% completed 3-month follow-up. Intervention participants reported high satisfaction with the personalized booklet (mean = 8.6, SD = 1.6; on a 0-10 scale) and genetic counseling (mean = 8.1, SD = 2.2). No significant behavioral effects at 3-month follow-up were identified between intervention and control groups overall: objectively measured standard erythemal doses per day [-16%; 95% confidence interval (CI), -43% to 24%] and sun protection index (0.05; 95% CI, -0.07 to 0.18). There was increased confidence identifying melanoma at 3 months (0.40; 95% CI, 0.10-0.69). Stratified by risk category, effect sizes for intentional tanning and some individual sun protection items appeared stronger for the average-risk group. There were no appreciable group differences in skin cancer-related worry or psychologic distress., Conclusions: Our results demonstrate feasibility and acceptability of providing personalized genomic risk of melanoma to the public., Impact: Genomic risk information has potential as a melanoma prevention strategy. Cancer Epidemiol Biomarkers Prev; 26(2); 212-21. ©2016 AACR., (©2016 American Association for Cancer Research.)

Objective: To verify the ability of a novel Canine Elbow Realignment Osteotomy (CERO) system for acute axial radial or ulnar lengthening to restore normal elbow congruency in a shortened radius cadaver model using assessment by computed tomography (CT)., Study Design: In vitro cadaver study., Animals: Five pairs of greyhound forelimbs from animals euthanatized for reasons unrelated to the study., Methods: CT of each elbow was performed (1) pre-operatively (pre-op), (2) after placement of a linear motor IMEX™ external skeletal fixator (ESF) on the radius with diaphyseal ostectomy and radial shorting of 1-5 mm (post-ESF), and (3) after CERO surgery to lengthen the radius proximal to the ostectomy site by an amount equal to the degree of radial shortening (post-CERO). The joint space at 7 loci on dorsal plane and 6 loci on sagittal plane reconstructions was measured to assess changes in joint congruity between pre-op, post-ESF, and post-CERO. Repeated measures ANOVA with post hoc comparisons were performed to compare measurements between the 3 groups., Results: Mean joint space measurements at most loci in the dorsal and sagittal planes were significantly different post-ESF compared with pre-op, confirming development of joint incongruency with the model. Post-CERO joint space measurements did not differ significantly compared with pre-op measurements, demonstrating the return to normal joint congruency using the CERO procedure., Conclusion: CERO surgery restored humeroradioulnar congruency in our cadaver model and may have application for acute correction of axial radial or ulnar incongruency in canine elbows secondary to elbow dysplasia or premature growth plate closure., (© Copyright 2016 by The American College of Veterinary Surgeons.)

In 1996, the Toronto Sunnybrook Regional Cancer Centre developed the Rapid Response Radiotherapy Program (RRRP). The objective of this clinic is to consult, simulate, plan, and treat patients with palliative radiotherapy on the same day. In 2004, the RRRP initiated a program to provide clinical and research experience to undergraduate students interested in health sciences. The purpose of this study is to review the 10-year (2004-2013) experience of the RRRP and to examine whether the goals of the student program have been met. Students who worked in the RRRP from 2004 to 2013 were contacted to complete a short survey regarding their overall experience with the program and their current endeavors. Student accomplishments were collected from an internal database as well as PubMed. Descriptive statistics were used to analyze results. A total of 54 students from ten postsecondary institutions have worked in the RRRP; 29 were from the University of Waterloo undergraduate co-op program. In total, 214 articles with first authorship from students were published, 93 (43%) of which can be found on PubMed. Other accomplishments include 40 book chapters, 58 invited presentations, and 99 awards cumulatively. Qualitative data regarding student perspectives of their experience in the RRRP were also analyzed. Over the past 10 years, the RRRP has achieved its goal of providing quality medical and research experience to students interested in the health sciences. Using the responses of past and present students, we hope to continue to shape our program and provide unique opportunities to future students.

Introduction: In this study we examined whether females with the fragile X-associated tremor ataxia syndrome (FXTAS) and non-FXTAS premutation carriers have electrophysiological signs of underlying peripheral neuropathy., Methods: Nerve conduction studies (NCS) were performed on 19 women with FXTAS, 20 non-FXTAS carriers, and 26 age-matched controls. The results were compared with existing data on corresponding male carriers., Results: Women with FXTAS and non-FXTAS carriers had reduced sensory nerve action potential amplitudes. Also, there was a strong trend for reduced compound muscle action potential amplitudes in women with FXTAS, but not in non-FXTAS carriers. No significant slowing of nerve conduction velocities, prolongation of F-wave latencies, or associations with molecular measures was observed., Conclusions: This study suggests an underlying axonal neuropathy in women with FXTAS. However, in comparison to men with FXTAS, the NCS abnormalities in women were less severe, possibly due to the effect of a normal X chromosome., (© 2014 Wiley Periodicals, Inc.)

It is imperative that nurses caring for children, young people and their families develop and maintain effective, trusting and collaborative therapeutic relationships that sit within the scope of professional boundaries. This relationship is the nurse's responsibility and should be positive and mutually acceptable to all stakeholders. A unique challenge for children's nurses is to address and prioritise the child's care needs, while meeting the needs of, and empowering, the family. The 6Cs--care, compassion, competence, communication, courage, commitment--should underpin care and enable nurses to overcome challenges such as time pressures, acute situations or disturbed family expectation. Confidentiality and safeguarding should always be observed.

Associative learning is encoded under anesthesia and involves the medial prefrontal cortex (mPFC). Neuronal activity in mPFC increases in response to a conditioned stimulus (CS+) previously paired with an unconditioned stimulus (US) but not during presentation of an unpaired stimulus (CS-) in anesthetized animals. Studies in conscious animals have shown dissociable roles for different mPFC subregions in mediating various memory processes, with the prelimbic (PL) and infralimbic (IL) cortex involved in the retrieval and extinction of conditioned responding, respectively. Therefore PL and IL may also play different roles in mediating the retrieval and extinction of discrimination learning under anesthesia. Here we used in vivo electrophysiology to examine unit and local field potential (LFP) activity in PL and IL before and after auditory discrimination learning and during later retrieval and extinction testing in anesthetized rats. Animals received repeated presentations of two distinct sounds, one of which was paired with footshock (US). In separate control experiments animals received footshocks without sounds. After discrimination learning the paired (CS+) and unpaired (CS-) sounds were repeatedly presented alone. We found increased unit firing and LFP power in PL and, to a lesser extent, IL after discrimination learning but not after footshocks alone. After discrimination learning, unit firing and LFP power increased in PL and IL in response to presentation of the first CS+, compared to the first CS-. However, PL and IL activity increased during the last CS- presentation, such that activity during presentation of the last CS+ and CS- did not differ. These results confirm previous findings and extend them by showing that increased PL and IL activity result from encoding of the CS+/US association rather than US presentation. They also suggest that extinction may occur under anesthesia and might be represented at the neural level in PL and IL., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Health policies across western societies have embedded the need for service user and carer perspectives in service design and delivery of educational programmes. There is a growing recognition of the need to include the perspectives of children and young people as service users in the design and delivery of child focused educational programmes. Digital storytelling provides a strategy for student nurses to gain insight into the lived experiences of children and young people. Engaging with these stories enables students to develop an understanding of a young persons' experience of healthcare. This paper outlines a project that developed a digital learning object based upon a young person's experience of cancer and student evaluations of the digital learning object as a teaching and learning strategy. Over 80% of students rated the digital learning object as interesting and were motivated to explore its content. In addition, the evaluation highlighted that listening to the young person's experiences of her treatment regimes was informative and assisted understanding of a patients' perspective of care delivery., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

This article reports the development of natural history and active treatment benchmarks for psychological treatments of chronic pain. The benchmarks were derived from randomized controlled trials (RCTs) reported in a published meta-analysis. In two preliminary studies we surveyed small samples of active clinicians working in U.K. pain management programs. Study 1 assessed the fit between routine clinical treatment and the selected RCTs. In study 2 Delphi methodology was used to determine a set of outcome domains to be used in the development of benchmarks. In study 3 we extracted data from a set of RCTs where both pre- and post-treatment data were reported. Measures were allocated to 1 of 5 outcome domains (cognitive coping and appraisal, pain experience, pain behavior, emotional functioning, and physical functioning). Pre-treatment to post-treatment effect sizes (Cohen's d) were computed and, where necessary, aggregated within trial so that each trial contributed a single estimate to outcome domain. Effect size (ES) benchmarks were computed for all trials and those trials with an explicit cognitive behavior therapy protocol. In no case did the ES estimates for the untreated control deviate from 0. The average ES across outcome domains for the treatment arms was approximately 0.35. These benchmarks may be used to assess the effectiveness of routine clinical treatments for chronic pain. The application of these data and the limitations of the study are discussed., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Background: Management of cardiovascular risk factors includes commitment from patients to adhere to prescribed medications and adopt healthy lifestyles. Unfortunately many fail to take up and maintain the four key healthy behaviours (not smoking, having a balanced diet, limiting alcohol consumption and being more active). Five factors (beliefs, knowledge, transport and other costs, emotions, and friends and family support) are known to predict uptake of lifestyle behaviour change. The key factors influencing maintenance of healthy lifestyles are not known but would be helpful to support the development of relapse prevention programmes for this population. Our review aimed to clarify the main patient perceived factors thought to influence maintenance of changed healthy lifestyles., Methods: We performed a systematic review of qualitative observational studies and applied the principles of content synthesis and thematic analysis to extract reported factors (barriers and facilitators) considered by individuals to be influential in maintaining changed healthy lifestyle behaviours. Factors were then organised into an existing framework of higher order categories which was followed by an analysis of the interrelationships between factors to identify key themes., Results: Twenty two studies met our inclusion criteria. Participants reported barriers and facilitators within 13 categories, the majority of which were facilitators. The most commonly reported influences were those relating to social support (whether provided formally or informally), beliefs (about the self or the causes and management of poor health, and the value of maintaining lifestyle behaviours), and other psychological factors (including attitude, thinking and coping styles, and problem solving skills). Physical activity was the most commonly investigated behaviour in four categories, but overall, the main barriers and facilitators were related to a range of behaviours. Through analysis of the interrelationships between factors within categories, 'social support', 'education and knowledge', and 'beliefs and emotions' were all considered key themes., Conclusions: Our review suggests that for the most part, factors that influence lifestyle change are also important for maintaining healthy behaviours. This indicates that addressing these barriers and facilitators within lifestyle support programmes would also be of value in the longer-term.

Associative learning can occur under anesthesia and its neural correlates have begun to be elucidated. During discrimination learning under anesthesia in rats, lateral amygdala excitability increases in response to a conditioned stimulus (CS+) previously paired with electrical stimulation of the paw but not to another stimulus presented alone (CS-). Similarly, medial prefrontal cortex activity increases selectively during CS+ presentation after discrimination learning but this occurs only in neurons receiving input from the basolateral amygdala (BLA), the main source of amygdaloid projections to this region. However, BLA activity during discrimination learning under anesthesia has not been investigated. Here we used in vivo electrophysiology to examine BLA activity before and after associative learning and during later memory retrieval in anesthetized rats. We examined extracellular unit and local field potential (LFP) activity using an auditory discrimination learning paradigm. Rats were repeatedly presented with two distinct sounds, one of which was paired with electrical stimulation of the paw. One hour later, the paired sound (CS+) was presented alone along with the sound not paired with electrical stimulation (CS-). We found increased unit firing late (1 h) but not early (5 min) after learning. LFP power was increased both early and late after learning. In control experiments we also found increased unit and LFP activity late after electrical stimulation alone. After discrimination learning, unit firing increased in response to CS+, but not CS-, presentation. LFP power also showed a modest increase during CS+, compared to CS-, presentation. These findings suggest that discrimination learning under anesthesia can occur at the neural level in BLA. The potential relevance of these results is discussed in relation to previous studies examining neural activity during fear learning and memory processing in conscious animals., (Copyright © 2012 IBRO. Published by Elsevier Ltd. All rights reserved.)

As HIV-1 evolves over the course of infection, resistance against antiretrovirals may arise in the absence of drug pressure, especially against receptor and fusion blockers because of the extensive changes observed in the envelope glycoprotein. Here we show that viruses from the chronic phase of disease are significantly less sensitive to CCR5 receptor and fusion blockers compared to early infection variants. Differences in susceptibility to CCR5 antagonists were observed in spite of no demonstrable CXCR4 receptor utilization. No significant sensitivity differences were observed to another entry blocker, soluble CD4, or to reverse transcriptase, protease, or integrase inhibitors. Chronic as compared to early phase variants demonstrated greater replication when passaged in the presence of subinhibitory concentrations of fusion but not CCR5 receptor inhibitors. Fusion antagonist resistance, however, emerged from only one chronic phase virus culture. Because sensitivity to receptor and fusion antagonists is correlated with receptor affinity and fusion capacity, respectively, changes that occur in the envelope glycoprotein over the course of infection confer greater ability to use the CCR5 receptor and increased fusion ability. Our in vitro passage studies suggest that these evolving phenotypes increase the likelihood of resistance against fusion but not CCR5 receptor blockers.

Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man., (Crown Copyright © 2011. Published by Elsevier Ltd. All rights reserved.)

The objective of the study was to estimate the prevalence and incidence of Mycoplasma bovis, a common cause of pneumonia, in veal calves. Using simple random sampling, 252 calves from 4 veal herds located in central Pennsylvania were selected and longitudinally followed for monthly collection of nasal swabs. Bronchial swabs and lung lesions were collected at the slaughterhouse. Nasal, bronchial, and lung lesion swabs were cultured for bacterial respiratory pathogens. Ninety lung lesions were identified, of which 41.1, 1.1, 1.1, 7.8, and 4.4% were culture positive for M. bovis alone, Pasteurella multocida alone, Mannheimia haemolytica alone, M. bovis and P. multocida co-infection, and M. bovis and M. haemolytica co-infection, respectively. The data indicate that potential interventions, such as therapeutics, vaccines, or management control measures, would be most effective before 50 d of age based upon the cumulative incidence of colonization., (Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.)

Osteoarthritis (OA) is a widespread degenerative disease of skeletal joints and is often associated with senescence in vertebrates. OA commonly results from excessive or abnormal mechanical loading of weight-bearing joints ('wear-and-tear'), arising from heavy long-term use or specific injuries; yet, in the absence of injury, the aetiology of OA remains obscure. We show that poor nutritional conditions experienced by moose (Alces alces) early in life are linked to greater prevalence of OA during senescence as well as reduced life expectancy. Moreover, we also found a negative relationship between kill rate by wolves (Canis lupus) and prevalence of OA, suggesting a potential connection between senescence of prey and the population ecology of predator-prey systems. This association between OA and early malnutrition also provides a basis for explaining the observation in anthropology that OA became more prevalent in native Americans as their diet become poorer - the result of relying more on corn and agriculture and less on hunting and gathering.

Background and Purpose: Prostanoid EP(4) receptor antagonists may have therapeutic utility in the treatment of migraine since EP(4) receptors have been shown to be involved in prostaglandin (PG)E(2)-induced cerebral vascular dilatation, which may be an important contributor to migraine pain. This study reports the pharmacological characterization of BGC20-1531, a novel EP(4) receptor antagonist., Experimental Approach: BGC20-1531 was characterized in radioligand binding and in vitro functional assays employing recombinant and native EP(4) receptors. Changes in canine carotid haemodynamics were used to assess the pharmacodynamic profile of BGC20-1531 in vivo., Key Results: BGC20-1531 exhibited high affinity at recombinant human EP(4) receptors expressed in cell lines (pK(B) 7.6) and native EP(4) receptors in human cerebral and meningeal artery (pK(B) 7.6-7.8) but showed no appreciable affinity at a wide range of other receptors (including other prostanoid receptors), channels, transporters and enzymes (pKi < 5). BGC20-1531 competitively antagonized PGE(2)-induced vasodilatation of human middle cerebral (pK(B) 7.8) and meningeal (pK(B) 7.6) arteries in vitro, but had no effect on responses induced by PGE(2) on coronary, pulmonary or renal arteries in vitro. BGC20-1531 (1-10 mg.kg(-1) i.v.) caused a dose-dependent antagonism of the PGE(2)-induced increase in canine carotid blood flow in vivo., Conclusions and Implications: BGC20-1531 is a potent and selective antagonist at EP(4) receptors in vitro and in vivo, with the potential to alleviate the symptoms of migraine that result from cerebral vasodilatation. BGC20-1531 is currently in clinical development for the treatment of migraine headache.

Tryptase is a serine protease found almost exclusively in mast cells. It has trypsin-like specificity, favoring cleavage of substrates with an arginine (or lysine) at the P1 position, and has optimal catalytic activity at neutral pH. Current evidence suggests tryptase beta is the most important form released during mast cell activation in allergic diseases. It is shown to have numerous pro-inflammatory cellular activities in vitro, and in animal models tryptase provokes broncho-constriction and induces a cellular inflammatory infiltrate characteristic of human asthma. Screening of in-house inhibitors of factor Xa (a closely related serine protease) identified beta-amidoester benzamidines as potent inhibitors of recombinant human betaII tryptase. X-ray structure driven template modification and exchange of the benzamidine to optimize potency and pharmacokinetic properties gave selective, potent and orally bioavailable 4-(3-aminomethyl phenyl)piperidinyl-1-amides.

Evidence is presented that adds to the debate surrounding the question: To what extent does neural control of cardiac output exploit noise? The transduction capability of cardiac afferent neurons, situated in and adjacent to the heart, is vital to feedback in control of cardiac function. An analysis of in situ cardiac afferent activity shows evidence of independent and exponentially distributed interspike intervals. An anatomical basis for such memoryless interspike intervals ultimately derives from the fact that each afferent neuron is associated with a field of sensory neurites, or bare nerve endings, that transduce local chemical and mechanical stimuli in a many-to-one fashion. As such, cardiac afferent neurons and their sensory neurite inputs are respectively modeled here by the Hodgkin-Huxley equations forced by "red" noise (decaying power spectrum) perturbing an otherwise constant subthreshold input. A variable barrier competition model is derived from these equations in order to address the question: How are noisy inputs being processed by sensory neurons to cause each spike? It is found that ion channels are responsible for significant input "whitening" (increased spectral power at higher frequency) through differentiation of the inputs. Such whitening is a means to distinguish low-frequency control signals from otherwise red noise fluctuations. Furthermore, spiking occurs when backward moving averages of the whitened inputs, over a window of the order of the sodium activation time scale, exceed an approximately constant barrier.

The utilization and impact of parallel synthesis on lead exploration around initial hit oxindole (1) are described. The emergent SAR, analogue design and functional impact will also be detailed.

A series of oxindoles demonstrating inhibition of the phosphorylation of biotinylated substrates of Syk and IgE/Fc epsilon RI triggered basophil cell degranulation has been identified. A study of the SAR around sulfonamide 31 (IC(50)=5 nM, EC(50)=1400 nM) is discussed. The modest cellular activity representative of the sulfonamide series was overcome when the Polar Surface Area was lowered to <110 A(2), leading to the identification of amide 32 (IC(50)=145 nM, EC(50)=100 nM).

The purpose of this study was to examine adaptive behaviour profiles in children with autism and moderate to severe developmental delay. Previous research has found that children with autism present a characteristic pattern of adaptive behaviour, as measured by the Vineland Adaptive Behavior Scales (VABS) (deficit in the domain of socialization, relative deficit in the domain of communication and relative strength in the domain of daily living). In this study VABS were administered (as part of a comprehensive evaluation of abilities) to a sample of 50 children with moderate to severe developmental delay (23 children with autism and 27 chronological and developmental age matched non-autistic children). Contrary to initial predictions, the sample presented fairly homogeneous adaptive behaviour profiles. Results are discussed with respect to the effectiveness of adaptive behaviour profiles in the detection of autism and the importance of employing limited chronological and developmental age ranges in the study of autism in infancy.

Aim of the study was (1) to evaluate sensorimotor development of children with autism in comparison with that of children with developmental delay, (2) to verify the possible unevenness of the developmental profiles through correlations amongst domains and between domains and chronological age. 46 children with autism were compared with 45 children with developmental delay. Mean chronological age was 3.7 yr. in children with autism and 3.6 yr. in children with mental retardation. Mean mental age was 1.3 yr. in children with autism and 1.1 yr. in children with developmental delay. Ordinal scales of Uzgiris-Hunt show that the two groups score significantly differently on the scales of Object Permanence, Means-Ends, Operational Causality, and Spatial Relations and that scores were higher for the children with autism. The comparison made between the developmental levels of each group indicate that the sensorimotor profile in children with developmental delay is fairly homogeneous, while it appears uneven in autistic children, for whom Object Permanence appears to be the most advanced skill, Verbal and Gestural Imitation and Schemes for Relating to Objects the lowest. The results are in keeping with the assumption that the pivotal defect of autism is a deficit in social interactive skills.

The myasthenic syndrome due to abnormal acetylcholine resynthesis is characterized by early onset, recessive inheritance, and recurrent episodes of potentially fatal apnea. Mutations in the gene encoding choline acetyltransferase (CHAT) have been found to account for this condition. We have identified five patients from three independent families with features of this disease including, in four patients, a paradoxical worsening of symptoms with cold temperatures. Electrodiagnostic studies demonstrated impaired neuromuscular transmission in all patients. In vitro microelectrode studies performed in the anconeus muscle biopsies of two patients showed moderate reduction of quantal release. Electron microscopy of the neuromuscular junction was normal in both patients. Each patient had two heterozygous CHAT mutations including L210P and P211A (family 1), V194L and V506L (family 2), and R548stop and S694C (family 3). Three of these mutations have previously been reported and suggest that, in this syndrome, some molecular defects may be more prevalent than others.

The purpose of this study was to examine the effects of an external nasal strip (NS), frusemide (FR) and a combination of the 2 treatments (NS + FR) on exercise-induced pulmonary haemorrhage (EIPH) in Thoroughbred horses. It was hypothesised that both the NS and FR would attenuate EIPH as assessed by red blood cell count in bronchoalveolar lavage fluid. In random order, 8 horses completed each of 4 sprint exercise tests on a treadmill: 1) NS; 2) FR (0.5 mg/kg bwt i.v., 4 h pre-exercise); 3) NS + FR; and 4) control (C; no treatment). After a 5 min warm-up (4.5 m/s), horses completed 2 min running at 120% maximum oxygen consumption (VO2max) with the treadmill set at 3 degrees incline. Mean +/- s.d. running speed was 14.2+/-0.2 m/s. In the FR and NS + FR trials, horses carried weight equal to that lost as a result of frusemide administration. During exercise at 120% Vo2max, oxygen consumption (Vo2) and carbon dioxide production (Vco2) were measured at 15 s intervals. Plasma lactate concentration was measured in samples collected before exercise, at the end of the sprint and after 5 min cool-down at the trot. Thirty minutes after the run, bronchoalveolar lavage (BAL) was performed and the red cell count in the fluid quantified. Vo2 and Vco2 were significantly lower in NS and NS + FR trials than in the C and FR trials at the end of the sprint exercise protocol. However, plasma lactate concentrations did not differ among treatments. Compared with the C trial (61.1+/-30.5 x 10(6) red blood cells/ml BAL fluid), pulmonary haemorrhage was significantly (P<0.05) decreased in both the NS (15.9+/-4.0 x 106 RBC/ml) and FR (12.2+/-5.8 x 10(6) RBC/ml) trials. EIPH in the NS + FR trial (7.9+/-1.0 x 10(6) RBC/ml) was further diminished (P<0.05) compared to the NS trial, but not different from the FR trial. We conclude that both the external nasal strip and frusemide attenuate pulmonary haemorrhage in Thoroughbred horses during high-speed sprint exercise. The external nasal strip appears to lower the metabolic cost of supramaximal exertion in horses. Given the purported ergogenic effects of frusemide, the external nasal strip is a valuable alternative for the attenuation of EIPH.

Neuromuscular blocking agents are routinely used as an adjunct therapy for critically ill patients. Unlike many neuromuscular blocking agents, vecuronium does not cause significant histamine release, which may lead to bronchoconstriction. Due to a short duration of action and limited accumulation, vecuronium has been widely used. Prolonged ventilatory dependence due to persistent neuromuscular blockade has been reported in patients treated with vecuronium. We report a case of an 8-year-old girl who had a primarily motor axonopathy presenting with weakness after extended vecuronium administration with prolonged course of recovery. This primarily motor neuropathy with axonal features may be a variant of critical illness polyneuropathy, a rarely reported condition in pediatric patients.

The purpose of this investigation was to study the effects of an equine nasal strip (NS), furosemide (Fur), and a combination of both (NS + Fur) on exercise-induced pulmonary hemorrhage (EIPH) at speeds corresponding to near-maximal effort. Five Thoroughbreds (526 +/- 25 kg) were run on a flat treadmill from 7 to 14 m/s in 1 m x s(-1) x min(-)1 increments every 2 wk (treatment order randomized) under control (Con), Fur (1 mg/kg iv 4 h prior), NS, or NS + Fur conditions. During each run, pulmonary arterial (Ppa) and esophageal (Pes) pressures were measured. Severity of EIPH was quantified via bronchoalveolar lavage (BAL) 30 min postrun. Furosemide (Fur and NS + Fur trials) reduced peak Ppa approximately 7 mmHg compared with Con (P < 0.05) whereas NS had no effect (P > 0.05). Maximal Pes swings were not different among groups (P > 0.05). NS significantly diminished EIPH compared with the Con trial [Con, 55.0 +/- 36.2; NS, 30.8 +/- 21.8 x 10(6) red blood cells (RBC)/ml BAL fluid; P < 0.05]. Fur reduced EIPH to a greater extent than NS (5.2 +/- 3.0 x 10(6) RBC/ml BAL; P < 0.05 vs. Con and NS) with no additional benefit from NS + Fur (8.5 +/- 4.2 x 10(6) RBC/ml BAL; P > 0.05 vs. Fur, P < 0.05 vs. Con and NS). In conclusion, although both modalities (NS and Fur) were successful in mitigating EIPH, neither abolished EIPH fully as evaluated via BAL. Fur was more effective than NS in constraining the severity of EIPH. The simultaneous use of both interventions appears to offer no further gain with respect to reducing EIPH.

Regional cardiac control depends upon feedback of the status of the heart from afferent neurons responding to chemical and mechanical stimuli as transduced by an array of sensory neurites. Emerging experimental evidence shows that neural control in the heart may be partially exerted using subthreshold inputs that are amplified by noisy mechanical fluctuations. This amplification is known as aperiodic stochastic resonance (ASR). Neural control in the noisy, subthreshold regime is difficult to see since there is a near absence of any correlation between input and the output, the latter being the average firing (spiking) rate of the neuron. This lack of correlation is unresolved by traditional energy models of ASR since these models are unsuitable for identifying "cause and effect" between such inputs and outputs. In this paper, the "competition between averages" model is used to determine what portion of a noisy, subthreshold input is responsible, on average, for the output of sensory neurons as represented by the Fitzhugh-Nagumo equations. A physiologically relevant conclusion of this analysis is that a nearly constant amount of input is responsible for a spike, on average, and this amount is approximately independent of the firing rate. Hence, correlation measures are generally reduced as the firing rate is lowered even though neural control under this model is actually unaffected.

Although the ekcuodiagnostic abnormalities in botulism have bean well characterized, the expected abnormalities, such as facilitation of compound muscle anion potential amplitudes after sustained activation or with repetitive stimulation at fast tales, may not always be present especially early m the disease. This may lead to etectrodtagnosttc difficulties and sometimes a delay in establishing a diagnosis. We describe four serologically proven cases of type A botulism in adults that illustrate the variability in ekctrodiagnostic findings in this disease.

Aperiodic stochastic resonance (ASR) is studied for a densely interconnected population of excitatory and inhibitory neurons that exhibit hysteresis. Switching between states in the presence of noisy external forcing is represented as a "competition between averages" and this is further explained through a semianalytical model. In contrast to energy-based approaches where only the timing of a switch between states is represented, the competition between averages also identifies the input history responsible for a switch. This last point leads to some interesting conclusions regarding cause and effect in the presence of noisy forcing of a hysteretic system. For example, at subthreshold inputs, it is found that the input history causing a switch between states is primarily dependent upon the noise level even though the corresponding time to switch is sensitive to both the distance from the threshold and the noise level. Since the application considered here is to cardiac neuronal control, control performance is considered over the full input range. Noise tuning for adequate control performance is found to be unnecessary if the noise level is high enough. This is consistent with studies of ASR for sensory neurons. Another observation made here that may be of clinical significance is that at higher noise levels, constraints placed upon inputs to ensure adequate control performance are likely to depend upon the switching direction.

An electrocardiogram (ECG) compression algorithm based on a combination of the Karhunen-Loeve transform (KLT) and multirate sampling is introduced. The use of multirate sampling reduces KLT computational times to those reported for wavelet-packet-based compression techniques. A beat-by-beat quality controlled compression criterion is shown to be necessary to ensure clinically adequate reconstruction of each beat. The resulting quality controlled algorithm efficiently achieves compression rates of approximately 30-40:1 for the MIT-BIH database.

A case report of a 61 year-old male with a long history of complex partial seizures is presented. Multiple psychotic symptomatology developed post-operatively. It is argued that these reflect continuing right temporal epileptogenic activity.

Twenty-six people with Down's syndrome (DS) were investigated using 99Tc(m)-hexamethylpropylene amine oxime (99Tc(m)-HMPAO) and single photon emission tomography (SPET). Dementia was diagnosed using a structured carer interview giving a deterioration score and by studying the case notes. Five subjects were clinically demented, 7 showed mild deterioration and 14 no deterioration. Increased deterioration correlated with advancing age (correlation coefficient 0.5425; P<0.02), but there was no significant difference between older (>40 years) and younger (<40 years) patients. Only one of the subjects with dementia had a regional cerebral blood flow (rCBF) abnormality that was of the dementia of Alzheimer type. Three subjects with mild deterioration and three with no deterioration had abnormal SPET scans. There was no association between the SPET abnormality and clinical dementia or with evidence of deterioration.

Snoring is a significant problem both for the patient and for the bedpartner. It is well known that nasal stuffiness can contribute to snoring, and sleep quality may deteriorate because of the snoring. Nasal dilation can reduce snoring and improve sleep. Thirty-five habitual snorers (18 female, 17 male) and their bedpartners participated in an open label study. The patients were diagnosed as heavy snorers after they underwent overnight polysomnography showing that their apnoea indexes were below 5, thus sleep apnoea patients were not included in the study. The participants and their partners filled out evaluations concerning snoring intensity, mouth dryness and Epworth Sleepiness Scale prior to and after using Breath Right nasal strips for 14 consecutive nights. The Breathe Right external nasal dilator is a simple, nonpharmaceutical method to decrease nasal airway resistance and thus potentially reduce or eliminate snoring. After using the strips there were statistically significant decreases in snoring (p < 0.001) as graded by the bed partner, and in mouth dryness (p = 0.025) and in the Epworth Sleepiness Scale scores (p = 0.001), as graded by the patient. The results of this study indicate that Breathe Right nasal strips may be used to reduce snoring, mouth dryness and sleepiness in patients presenting with symptoms of snoring.

We report the case of a severely hypotonic and weak term newborn who required ventilatory support from the time of birth. Serial neurophysiologic studies were consistent with severe demyelinating polyneuropathy. The infant's condition deteriorated over several weeks despite treatment with corticosteroids and intravenous immunoglobulin (IVIG) for presumed inflammatory demyelinating polyneuropathy. Histopathologic findings in a sural nerve biopsy, however, were similar to those previously reported in congenital hypomyelinating neuropathies. After 12 weeks of hospitalization and after discontinuation of corticosteroids, the patient began to recover and required no further ventilatory support. Remarkable improvement has continued for 18 months. This patient raises questions about the underlying mechanisms of hypomyelinating neuropathies in early infancy.

Objective: To examine if different violent offending behaviours are associated with different clinical and neuroimaging profiles., Method: Thirty-nine schizophrenic and schizoaffective offenders from a maximum security mental hospital-20 repetitive violent offenders (RVOs) and 19 non-repetitive violent offenders (NRVOs)-were selected for clinical and neuroimaging assessments., Results: Both groups had positive family history of mental illness and violence. Age, diagnosis, duration of illness, victim profiles and use of weapons at the time of the index offence were similar. RVOs had a higher prevalence of early parental separation, juvenile conduct problem, previous convictions of crimes not involving violence, impulsive suicide attempts, delusion of their lives being threatened at the time of the index offence and electroencephalographic (EEG) abnormalities localized to temporal lobes. NRVOs had a higher prevalence of sexual inexperience and command hallucinations to kill at the time of the index offence. Asymmetric gyral patterns at the temporo-parietal region were particularly common in RVOs and absent in NRVOs. Non-specific white matter changes in magnetic resonance imaging (MRI) and generalized cortical hypometabolism in positron emission tomography (PET) were present in both groups., Conclusions: Different structural and metabolic changes in the brain were associated with different violent offending behaviours. The complex interaction between violent behaviour, clinical features and neuroimaging findings in schizophrenia requires further studies.

The FDG PET brain scans from 31 offenders with schizophrenia and schizoaffective disorder from a maximum security mental hospital were compared with those of normal controls (N = 6) in terms of relative FDG uptake in a range of regions covering frontal and temporal regions. The patient sample was divided into those who had a history of repetitive violent offending (RVO, N = 17) and those without a repetitive violent history (NRVO, N = 14) according to the violence rating of their pre-admission convictions. Reduced FDG uptake was noted at both the right and left anterior inferior temporal (R and L AIT) regions in NRVOs but only at LAIT in RVOs. NRVOs had significantly lower FDG uptake at RAIT than RVOs. The findings suggest that metabolic changes at AIT may be related to different patterns of violent offending in patients with schizophrenia.