A blockchain-based framework to support pharmacogenetic data sharing.

The successful implementation of pharmacogenetics (PGx) into clinical practice requires patient genomic data to be shared between stakeholders in multiple settings. This creates a number of barriers to widespread adoption of PGx, including privacy concerns related to the storage and movement of identifiable genomic data. Informatic solutions that support secure and equitable data access for genomic data are therefore important to PGx. Here we propose a methodology that uses smart contracts implemented on a blockchain-based framework, PGxChain, to address this issue. The design requirements for PGxChain were identified through a systematic literature review, identifying technical challenges and barriers impeding the clinical implementation of pharmacogenomics. These requirements included security and privacy, accessibility, interoperability, traceability and legal compliance. A proof-of-concept implementation based on Ethereum was then developed that met the design requirements. PGxChain's performance was examined using Hyperledger Caliper for latency, throughput, and transaction success rate. The findings clearly indicate that blockchain technology offers considerable potential to advance pharmacogenetic data sharing, particularly with regard to PGx data security and privacy, large-scale accessibility of PGx data, PGx data interoperability between multiple health care providers and compliance with data-sharing laws and regulations.

Suckling behavior of calves in seasonally calving pasture-based dairy systems, and possible environmental and management factors affecting suckling behaviors.

In recent years, interest has been increasing in whether farmed animals are able to live a reasonably natural life, with one particular area of concern being calf-dam separation. The objectives of this study were to monitor the timing and frequency of suckling behavior of calves left on pasture to suckle their dams for up to 24 h (interquartile range 4.0-15.5 h) and to investigate possible risk factors that may contribute to any variability seen. Over 2 yr, a convenience sample of 8 farms (4 in the North Island, 4 in the South Island of New Zealand) were involved in an observational study where cows and calves were observed for 24 h a day over a 2-wk-long period per farm. During the observation period, farmers continued to remove calves at the same frequency they normally did (which ranged from once a day to 4 times a day). Cows (between 2 and 12 yr old) and calves were observed from a scissor lift in or beside the calving paddock. Cows had numbers written on them, and observers used binoculars and spotlights. Observers recorded the length of stage 2 labor, time of birth, standing, and first suckling, number of suckling events, time of calf removal from the dam, temperature where the cows were grazing, and size of the grazing area they were calving in. Dams were body condition scored before calving, and their age was extracted from farm records. A total of 697 calves were observed during the study. A total of 444 of 697 calves [63.7%; 95% confidence interval (CI) = 60.0-67.3%] suckled in the calving paddock (farm range 40.0% to 90.2%). Of the 444 calves that suckled in the calving paddock, 407 (58.4%; 95% CI 54.6-62.1%) suckled within the first 6 h after birth (farm range 33.0% to 83.6%). Individual risk factors associated with the hazard rate ratio (HR) for time to first suckling event were time to standing (calves who took more than 1.3 h to stand had a longer time from birth to first suckle) and age of the dam [compared with calves that were born from dams >7 years of age, calves born to dams that were 2-3 and 4-7 yr of age had a 1.49 (95% CI 1.07-2.06) and 1.19 (95% CI 0.89-1.60) HR, respectively, for time from birth to first suckle in the calving paddock]. Farm risk factors associated with the HR of suckling were frequency of calf collection [calves that were born on farms that collected calves once a day suckled earlier than calves on farms that removed calves more than once a day (HR 1.52; 95% CI 1.25-1.84)] and temperature [a minimum temperature of <10°C within 6 h of a calf being born was associated with a 0.69 (95% CI 0.53-0.89) hazard of suckling in the calving paddock]. We observed very large farm variability that urgently requires further investigation if pasture-based farms are ever to adopt a system where calves remain with their dams for longer than 24 h.

Epidemic disease risks and implications for Veterinary Services.

Growth in the livestock sector is associated with heightened risk for epidemic diseases. The increasing spillover of new diseases from wildlife is being driven by wide-scale anthropogenic changes allowing for more frequent and closer wildlife-human and wildlife-livestock contacts. An increasing number of epidemics in livestock are associated with rapid transition of livestock systems from extensive to intensive, and local to global movement of livestock and their products through value chain networks with weak biosecurity. Major livestock epidemics in the past two decades have had substantial economic impacts, and the COVID-19 pandemic highlights the devastating socio-economic consequences that spillovers can have when not identified and controlled early in the process of emergence. This highlights the importance of Veterinary Services to integrated, whole-of-society efforts to control infectious diseases in animals. Emphasis within Veterinary Services must be placed on prevention and preparedness. The authors suggest four areas for continued improvement in Veterinary Services to meet this challenge. These are a) continued development of staff capacity for risk assessment and value chain analysis, together with improved policies and communication, b) appropriate adaptation of approaches to prevention and control in resource-poor settings, c) improved multi-sectoral and transboundary cooperation, which enables the sharing of resources and expertise, and d) systematic approaches that enable Veterinary Services to influence decisionmaking for trade, markets, business, public health, and livelihood development at the national and regional levels.

La croissance du secteur de l'élevage est associée à un risque accru de maladies épidémiques. Les changements anthropiques à grande échelle sont à l'origine du nombre croissant de maladies émergentes atteignant de nouvelles espèces réceptives (spillover) à partir de réservoirs sauvages, à la faveur de contacts plus fréquents et plus rapprochés entre la faune sauvage et les humains, d'une part, et entre la faune sauvage et les animaux domestiques, d'autre part. On considère qu'un nombre croissant d'épidémies affectant le bétail sont dues à la transition rapide des systèmes d'élevage extensif vers des systèmes intensifs, et aux mouvements du bétail et des produits de l'élevage de l'échelle locale à l'échelle mondiale par le biais de réseaux de chaînes de valeur dotés d'un faible niveau de biosécurité. Au cours des deux dernières décennies, d'importantes épidémies affectant le bétail ont eu un impact économique considérable ; en outre, la pandémie de COVID-19 a mis en évidence les conséquences socio-économiques dévastatrices des atteintes de nouvelles espèces réceptives par des agents pathogènes, lorsque ces maladies ne sont pas détectées et maîtrisées dès le processus d'émergence. Cela souligne l'importance cruciale des Services vétérinaires dans les efforts de lutte contre les maladies infectieuses chez les animaux, qui doivent être intégrés et mobiliser la société entière. Les Services vétérinaires doivent mettre un accent particulier sur la prévention et la préparation. Les auteurs proposent quatre aspects d'amélioration continue pour que les Services vétérinaires puissent relever ce défi. Il s'agit : a) du développement permanent des compétences des personnels vétérinaires en matière d'évaluation du risque et d'analyse des chaînes de valeur, et leur articulation avec de meilleures politiques et une communication plus performante ; b) une adaptation adéquate des méthodes de prévention et de contrôle dans les configurations faiblement dotées en ressources ; c) une meilleure coopération multisectorielle et transfrontalière afin de partager les ressources et les compétences ; d) des dispositifs systémiques permettant aux Services vétérinaires d'influencer les prises de décision en matière d'échanges internationaux, de marchés, de commerce, de santé publique et de développement des moyens de subsistance, à l'échelle nationale et régionale.

El crecimiento del sector pecuario está condicionado por la existencia de un mayor riesgo de enfermedades epidémicas. La creciente diseminación de nuevas enfermedades a partir de animales silvestres es consecuencia de transformaciones antrópicas a gran escala que posibilitan un contacto más frecuente y estrecho de la fauna silvestre con el ser humano y el ganado. Cada vez son más las epidemias del ganado que tienen que ver con la rápida transición de los sistemas pecuarios de un régimen de producción extensiva a otro de producción intensiva y con el paso de la dimensión local a la mundial de la circulación de animales y sus derivados a través de redes de cadenas de valor que presentan una endeble seguridad biológica. En los últimos dos decenios ha habido grandes epidemias que han afectado al ganado y tenido importantes consecuencias económicas. La pandemia de COVID-19 es un elocuente ejemplo de los devastadores efectos socioeconómicos que puede tener la extensión de un patógeno cuando no se detecta y controla en un momento lo bastante precoz del proceso de emergencia. Ello pone de relieve la importancia que revisten los Servicios Veterinarios para que toda la sociedad pueda reaccionar de forma integrada a la hora de combatir las enfermedades infecciosas de los animales. Dentro de los Servicios Veterinarios, conviene poner el acento en la prevención y la preparación. Para lograr este objetivo los autores señalan cuatro ámbitos que exigen una constante mejora: a) el desarrollo continuo de la capacidad del personal en materia de determinación de riesgos y análisis de cadenas de valor, ligado a la mejora de las políticas y la comunicación; b) la adecuada adaptación de los métodos de prevención y control en contextos de escasos recursos; c) una mejor cooperación multisectorial y transfronteriza, que permita poner en común recursos y competencias técnicas; y d) enfoques sistemáticos que hagan posible que los Servicios Veterinarios influyan en los procesos decisorios relativos al desarrollo del comercio, los mercados, las empresas, la salud pública y los medios de sustento a escala tanto nacional como regional.

Effects of a topically applied anaesthetic on the behaviour, pain sensitivity and weight gain of dairy calves following thermocautery disbudding with a local anaesthetic.

Aims: To compare the effect of a topically applied anaesthetic to no pain relief or meloxicam on the behavioural responses, pain sensitivity and weight gain of calves following disbudding with or without sedation. Methods: A total of 364, 2-6 week-old calves from three commercial farms were systematically allocated to one of six treatment groups. All calves received a cornual nerve block prior to disbudding, with half restrained in a crate and half sedated with xylazine. Within these groups one third received no further treatment (control), one third were treated with meloxicam >10 minutes prior to disbudding and one third received a topical anaesthetic applied to the horn bud wounds following disbudding. The frequency of ear flicks, head shakes, head scratches and pain sensitivity of the wound were recorded on up to eight occasions over 24 hours after disbudding. Calves were weighed before, and 7 and 28 days after, disbudding to determine average daily weight gain (ADG). Results: Compared to calves in the crate-control group, all other groups had reduced ear flicks at all times following disbudding (p < 0.01). Treatment with meloxicam and topical anaesthesia in addition to sedation reduced head scratches compared to calves in the crate-control group (p ≤ 0.013). At 22 hours after disbudding head shakes were reduced in sedated calves treated with topical anaesthetic compared to calves in the crate-control group (p < 0.001). Pain sensitivity was lower in all sedated calves than unsedated calves (p < 0.001). The ADG between Days 0-7 was 0.14 (95% CI = 0.015-0.274) kg/day greater in sedated calves treated with meloxicam than calves in the crate-control group (p = 0.03), and the ADG between Days 0-28 tended to be 0.06 (95% CI=-0.01-0.13) kg/day greater in sedated calves treated with topical anaesthetic than calves in the crate-control group (p = 0.09). Conclusion and clinical relevance: Sedation of calves for disbudding reduced the pain experienced in the following 24 hours. There was a benefit to providing calves with topical anaesthetic following disbudding on behavioural responses and pain sensitivity, which was similar to that of treating calves with meloxicam.

Hypoglycaemia represents a clinically significant manifestation of PIK3CA- and CCND2-associated segmental overgrowth.

The PI3K-AKT signalling cascade has a highly conserved role in a variety of processes including cell growth and glucose homoeostasis. Variants affecting this pathway can lead to one of several segmental overgrowth disorders. These conditions are genetically heterogeneous and require tailored, multidisciplinary involvement throughout life. Hypoglycaemia is common in other overgrowth syndromes but has been described only sporadically in association with PIK3CA and CCND2 variants. We report a cohort of 6 children with megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes who developed clinically significant hypoglycaemia. Based on our findings, we suggest that segmental overgrowth patients should be screened for low blood glucose levels during childhood and there should be early specialist endocrine review in any children who develop hypoglycaemia.

Comprehensive genomic profiling of salivary mucoepidermoid carcinomas reveals frequent BAP1, PIK3CA, and other actionable genomic alterations.

Background: We sought to identify genomic alterations (GAs) in salivary mucoepidermoid carcinomas. Patients and methods: DNA was extracted from 48 mucoepidermoid carcinomas. Comprehensive genomic profiling (CGP) including the calculation to tumor mutational burden (TMB) was performed on hybridization-captured adaptor ligation-based libraries of 315 cancer-related genes plus introns from 28 genes frequently rearranged for cancer and evaluated for all classes of GAs. Results: A total of 183 GAs were found in 80 unique genes. High-grade tumors had more GAs (mean 5 ± 3.8) compared with low (2.3 ± 1.4) or intermediate (2.6 ± 1.5) (P = 0.019). TP53 GAs were seen in all tumor grades (41.7%) but were most common in high-grade malignancies (56%) (P = 0.047). CDKN2A GAs were seen in 41.6% of tumors. PI3K/mTOR pathway activation, including PI3KCA mutations, were more common in high grade (52%) than in low- and intermediate-grade tumors (4.3%) (P = 0.007). BAP1 GAs were observed in 20.8% of tumors and BRCA1/2 GAs present in 10.5% of specimens. ERBB2 amplifications were seen in only 8.3% of tumors. The TMB for this patient group was relatively low with only 5 (10%) of cases having greater than 10 mutations/megabase of sequenced DNA. Conclusion: CGP of salivary mucoepidermoid carcinomas revealed diverse GAs that may lead to customized treatment options for patients with these rare tumors.

The use of a cartilage decellularized matrix scaffold for the repair of osteochondral defects: the importance of long-term studies in a large animal model.

OBJECTIVE: To investigate the effect of decellularized cartilage-derived matrix (CDM) scaffolds, by itself and as a composite scaffold with a calcium phosphate (CaP) base, for the repair of osteochondral defects. It was hypothesized that the chondral defects would heal with fibrocartilaginous tissue and that the composite scaffold would result in better bone formation. METHODS: After an 8-week pilot experiment in a single horse, scaffolds were implanted in eight healthy horses in osteochondral defects on the medial trochlear ridge of the femur. In one joint a composite CDM-CaP scaffold was implanted (+P), in the contralateral joint a CDM only (-P) scaffold. After euthanasia at 6 months, tissues were analysed by histology, immunohistochemistry, micro-CT, biochemistry and biomechanical evaluation. RESULTS: The 8-week pilot showed encouraging formation of bone and cartilage, but incomplete defect filling. At 6 months, micro-CT and histology showed much more limited filling of the defect, but the CaP component of the +P scaffolds was well integrated with the surrounding bone. The repair tissue was fibrotic with high collagen type I and low type II content and with no differences between the groups. There were also no biochemical differences between the groups and repair tissue was much less stiff than normal tissue (P < 0.0001). CONCLUSIONS: The implants failed to produce reasonable repair tissue in this osteochondral defect model, although the CaP base in the -P group integrated well with the recipient bone. The study stresses the importance of long-term in vivo studies to assess the efficacy of cartilage repair techniques.

Case study: failure of superior capsular reconstruction using dermal allograft.

Superior capsular reconstruction (SCR) is a novel technique for treating irreparable rotator cuff tears in younger patients in whom a reverse total shoulder arthroplasty is not the optimal treatment choice. This case study describes a middle-aged male with a recurrent, massive, irreparable rotator cuff tear treated with SCR that subsequently failed at the glenoid attachment. The patient underwent successful arthroscopic revision of the SCR. The case illustrates the MRI and arthroscopic correlations of the failed dermal allograft reconstruction, which to our knowledge has not been previously shown in the radiology literature.

Calf and replacement heifer mortality from birth until weaning in pasture-based dairy herds in New Zealand.

The aims of this study were to (1) estimate the perinatal (birth to 24 h) and postnatal (∼24 h to the mean weaning age of 13 wk) mortality risk in pasture-based dairy calves until weaning, and (2) identify associated risk factors in the 2015 calving season. A prospective survey of 32 seasonal calving dairy farms was undertaken. Farmers recorded (daily) the number and sex of the calves alive or dead in the paddocks where cows calved. All daily animal movements in and out of the calf rearing facilities, including death and euthanasia, and the identification of the animals (if applicable) were recorded, and a survey of the farm management practices was undertaken. Individual and farm-level risk factors for perinatal mortality were modeled separately using generalized logistic mixed models with a random effect fitted for herd. Postnatal mortality incidence risk was calculated using time at risk for each calf from 24 h of age, collapsed into weeks, and multiplying the incidence risk by the mean weaning age of the study population. Farm-level risk factors contributing to postnatal mortality in the first week of life were assessed using a multivariable logistic mixed regression model. The mean perinatal mortality risk was 5.7% (95% confidence interval 5.4 to 6.1%) with a range from 2.2 to 8.6% (18,437 calves, 30 farms). Perinatal calf mortality was greater for male relative to female calves (odds ratio 1.39; 95% confidence interval 1.22 to 1.59), calves born in the first week of the calving period in comparison to wk 2 to 11 (odds ratio 0.32 to 0.66), and those born on days with greater rainfall (odds ratio 1.01 per 1 mm increase; 95% confidence interval 1.00 to 1.02). At the farm level, perinatal mortality increased for every extra week of calving period length (odds ratio 1.12; 95% confidence interval 1.06 to 1.17). The mean postnatal mortality risk was 4.1% (95% confidence interval 3.6 to 4.6%) with a range of 0 to 11% between farms. Farm-level risk factors contributing to mortality in the first week of life included farmer-reported disease problems in calves (odds ratio 2.2; 95% confidence interval 1.62 to 2.96), or calves hand-fed colostrum in the first 12 h of life (odds ratio 1.66; 95% confidence interval 1.26 to 2.19), which was assumed to be associated with poor colostrum quality and bacterial contamination. Regional differences were also observed in both perinatal and postnatal mortality risks, indicating that weather conditions, herd size, and management variations contribute to mortality incidence. In summary, the mortality risk of perinatal calves and postnatal calves until weaning on pasture-based farms is comparable with data published from other dairying systems despite the notable management differences. Several risk factors were identified that could be managed to reduce mortality incidence of dairy calves.

Prevalence and calf-level risk factors for failure of passive transfer in dairy calves in New Zealand.

AIM To determine the prevalence of failure of passive transfer (FPT) in dairy calves in New Zealand and to assess a range of potential calf-level risk factors for their association with FPT. METHOD Between July and September 2015, 107 dairy farms in nine regions across New Zealand were visited on three occasions: before 20% of cows had calved, when ∼50% of cows had calved, and when the last 10-20% of cows were calving. Farms were randomly selected from the client list of participating veterinary practices. On each farm, blood samples were collected from 10-20 calves between 24 hours and 8 days old and concentrations of total protein (TP) in serum determined. Calf identification, date of birth, dam's age and breed, details of colostrum feeding and the farmer's health assessment of the calf on arrival at the calf rearing facility were recorded. Concentrations of TP in serum ≤52 g/L were used to define FPT. RESULTS Of 3,819 calves sampled, 1,263 (33 (95% CI=31.6-34.6)%) were diagnosed with FPT, and the prevalence within farms ranged from 5-83%. Calf-level risk factors that were associated with increased odds of FPT were increasing age of dam (OR=1.12; 95% CI=1.08-1.16), calves recorded as unhealthy compared to healthy upon arrival at the calf rearing facility (OR=2.59; 95% CI=1.60-4.19), calves sampled on farms in Otago (OR=2.85; 95% CI=1.42-5.74) and Southland (OR 2.31; 95% CI=1.15-4.67) compared to the Far North, and calves sampled in the middle compared to the early calving period (OR=1.24; 95% CI=1.03-1.51). CONCLUSION On the farms visited FPT was diagnosed in one third of dairy calves. Calf-level risk factors for FPT included age of dam, health status of calf, region, and time of the calving period. Further investigations are required to establish why these are associated with increased odds of FPT. CLINICAL RELEVANCE These results provide a baseline for benchmarking, which, alongside the reported calf-level risk factors, can be used by veterinarians to improve colostrum management.

Solid organ transplantation from hepatitis B virus-positive donors: consensus guidelines for recipient management.

Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non-liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti-HBc+) donors. Organs from anti-HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non-liver recipients but is not recommended in immune non-liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost-effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.

Regional deposition of mometasone furoate nasal spray suspension in humans.

Nasal deposition studies can demonstrate whether nasal sprays treating allergic rhinitis and polyposis reach the ciliated posterior nasal cavity, where turbinate inflammation and other pathology occurs. However, quantifying nasal deposition is challenging, because in vitro tests do not correlate to human nasal deposition; gamma scintigraphy studies are thus used. For valid data, the radiolabel must distribute, as the drug, into different-sized droplets, remain associated with the drug in the formulation after administration, and not alter its deposition. Some nasal deposition studies have demonstrated this using homogenous solutions. However, most commercial nasal sprays are heterogeneous suspensions. Using mometasone furoate nasal suspension (MFS), we developed a technique to validate radiolabel deposition as a surrogate for nasal cavity drug deposition and characterized regional deposition and nasal clearance in humans. Mometasone furoate (MF) formulation was spiked with diethylene triamine pentacaetic acid. Both unlabeled and radiolabeled formulations (n = 3) were sprayed into a regionally divided nasal cast. Drug deposition was quantified by high pressure liquid chromatography within each region; radiolabel deposition was determined by gamma camera. Healthy subjects (n = 12) were dosed and imaged for six hours. Scintigraphic images were coregistered with magnetic resonance imaging scans to quantify anterior and posterior nasal cavity deposition and mucociliary clearance. The ratio of radiolabel to unlabeled drug was 1.05 in the nasal cast and regionally appeared to match, indicating that in vivo radiolabel deposition could represent drug deposition. In humans, MFS delivered 86% (9.2) of metered dose to the nasal cavity, approximately 60% (9.1) of metered dose to the posterior nasal cavity. After 15 minutes, mucociliary clearance removed 59% of the initial radiolabel in the nasal cavity, consistent with clearance rates from the ciliated posterior surface. MFS deposited significant drug into the posterior nasal cavity. Both nasal cast validation and mucociliary clearance confirm the radiolabel deposition distribution method accurately represented corticosteroid nasal deposition.

A case-control study examining inconsistencies in pain management following fractured neck of femur: an inferior analgesia for the cognitively impaired.

Previous research suggests individuals who suffer from cognitive impairment are less able to vocalise pain than the rest of the cognitively-intact population. This feature of cognitive impairment may be leading to a chronic underdetection of pain as current assessment tools strongly rely on the participation of the patient. To explore inconsistencies in pain management within the acute setting, we conducted a retrospective assessment of 224 patients presenting with fractured neck of femur at a large teaching hospital's accident and emergency (A&E) department between 2 June 2011 and 2 June 2012. These patients were split into either a cognitively-impaired or cognitively-intact cohort based on their Abbreviated Mental Test Scores. Patients with cognitive impairment, on average, received a weaker level of analgesia than individuals without impairment both in the ambulance and in A&E. In the ambulance, 45% of cognitively-impaired patients were prescribed no pain relief compared with just 8% of those individuals who remain cognitively intact. After arrival at A&E, these inconsistencies continued with 69% of the cognitively-intact cohort receiving the strongest opioid analgesia compared with just 37% of the cognitively-impaired cohort. The cognitively-impaired cohort would also wait on average an hour longer before receiving this initial pain relief. We believe that these differences stem from cognitively-impaired patients being unable to vocalise their pain through traditional assessment methods. This work discusses the potential development or adoption of a tool which can be applied in the acute setting and relies less on vocalisation but more on the objective features of pain, so making it applicable to cognitively-impaired individuals.

Cross-talk between glycogen synthase kinase 3ß (GSK3ß) and p38MAPK regulates myocyte enhancer factor 2 (MEF2) activity in skeletal and cardiac muscle.

Characterizing the signaling network that controls MEF2 transcription factors is crucial for understanding skeletal and cardiac muscle gene expression. Glycogen synthase kinase 3ß (GSK3ß) regulates MEF2 activity indirectly through reciprocal regulation of p38MAPK. Cross-talk between GSK3ß and p38MAPK regulates MEF2 activity in skeletal and cardiac muscle. Understanding cross-talk in the signaling network converging at MEF2 control has therapeutic implications in cardiac and skeletal muscle pathology. Glycogen synthase kinase 3ß (GSK3ß) is a known regulator of striated muscle gene expression suppressing both myogenesis and cardiomyocyte hypertrophy. Since myocyte enhancer factor 2 (MEF2) proteins are key transcriptional regulators in both systems, we assessed whether MEF2 is a target for GSK3ß. Pharmacological inhibition of GSK3ß resulted in enhanced MEF2A/D expression and transcriptional activity in skeletal myoblasts and cardiac myocytes. Even though in silico analysis revealed GSK3ß consensus (S/T)XXX(S/T) sites on MEF2A, a subsequent in vitro kinase assay revealed that MEF2A is only a weak substrate. However, we did observe a posttranslational modification in MEF2A in skeletal myoblasts treated with a GSK3ß inhibitor which coincided with increased p38MAPK phosphorylation, a potent MEF2A activator, indicating that GSK3ß inhibition may de-repress p38MAPK. Heart specific excision of GSK3ß in mice also resulted in up-regulation of p38MAPK activity. Interestingly, upon pharmacological p38MAPK inhibition (SB203580), GSK3ß inhibition loses its effect on MEF2 transcriptional activity suggesting potent cross-talk between the two pathways. Thus we have documented that cross-talk between p38MAPK and GSK3ß signaling converges on MEF2 activity having potential consequences for therapeutic modulation of cardiac and skeletal muscle gene expression.

Risk factors associated with Clostridium difficile infection after kidney and pancreas transplantation.

BACKGROUND: Clostridium difficile infection (CDI) is a common cause of nosocomial antibiotic-associated diarrhea with an increased incidence reported in solid organ transplant recipients. We sought to determine if kidney and/or pancreas transplant recipients possess unique risk factors for CDI. METHODS: Between January 2009 and February 2011, 942 kidney and 56 pancreas transplants were performed at the 2 centers. Of these, 28 recipients (kidney, n = 24; pancreas, n = 4) developed CDI. Cases were matched to controls (n = 56) in a 1:2 ratio. RESULTS: Those with CDI were mostly male patients (82% vs. 48%, P = 0.003), deceased-donor organ recipients (86% vs. 64%, P = 0.045), more likely to have leukopenia (18% vs. 4%, P = 0.038), and had undergone a gastrointestinal procedure within 3 months preceding CDI diagnosis (18% vs. 4%, P = 0.038). Cases had higher cumulative and restricted antimicrobial exposure in days (37 ± 79 vs. 8 ± 12, P = 0.009 and 27 ± 69 vs. 7 ± 10, P = 0.032). Cephalosporin use was more common among cases (43% vs. 16%, P = 0.008). CONCLUSION: Careful antimicrobial selection and assurance of optimal treatment duration in the kidney and pancreas transplant population is prudent. Clinicians should have a heightened awareness of CDI risk particularly during periods of leukopenia and in the setting of gastrointestinal procedures.

Diverse styles of submarine venting on the ultraslow spreading Mid-Cayman Rise.

Thirty years after the first discovery of high-temperature submarine venting, the vast majority of the global mid-ocean ridge remains unexplored for hydrothermal activity. Of particular interest are the world's ultraslow spreading ridges that were the last to be demonstrated to host high-temperature venting but may host systems particularly relevant to prebiotic chemistry and the origins of life. Here we report evidence for previously unknown, diverse, and very deep hydrothermal vents along the approximately 110 km long, ultraslow spreading Mid-Cayman Rise (MCR). Our data indicate that the MCR hosts at least three discrete hydrothermal sites, each representing a different type of water-rock interaction, including both mafic and ultramafic systems and, at approximately 5,000 m, the deepest known hydrothermal vent. Although submarine hydrothermal circulation, in which seawater percolates through and reacts with host lithologies, occurs on all mid-ocean ridges, the diversity of vent types identified here and their relative geographic isolation make the MCR unique in the oceans. These new sites offer prospects for an expanded range of vent-fluid compositions, varieties of abiotic organic chemical synthesis and extremophile microorganisms, and unparalleled faunal biodiversity--all in close proximity.

Economics of brucellosis impact and control in low-income countries.

Most data and evidence on the economic burden of brucellosis and the benefits of its control are from high-income and middle-income countries. However, the burden of brucellosis is greatest in low-income countries. This paper focuses on estimating the economic burdens of brucellosis in low-income countries in tropical Asia and Africa. The prospects for national, technically feasible, and economically viable, national brucellosis control programmes in most low-income countries are limited. However, some targeted control programmes will be beneficial and can probably be feasibly managed and provide good economic returns. More ambitious control will require a more general strengthening of Veterinary Services and livestock-sector capacity, using risk-management-based approaches.

Central serous chorioretinopathy secondary to intramuscular testosterone therapy.

Summary: A patient treated with intramuscular testosterone replacement therapy for primary hypogonadism developed blurred vision shortly after receiving his testosterone injection. The symptom resolved over subsequent weeks and recurred after his next injection. A diagnosis of central serous chorioretinopathy (CSR) was confirmed following ophthalmology review. A decision was made to change the patient's testosterone regime from this 12-weekly intramuscular injection to a daily topical testosterone gel, given the possibility that peak blood levels of testosterone following intramuscular injection were causing his ocular complaint. His CSR did not recur after this change in treatment. CSR secondary to testosterone therapy is a rare finding but has been reported previously in the literature. Learning Points: Blurred vision in patients treated with testosterone replacement therapy (TRT) should prompt an ophthalmology review. The potential for reduced risk of central serous chorioretinopathy (CSR) with daily transdermal testosterone remains a matter of conjecture. CSR is a rare potential side effect of TRT.

Adapting lean methodology towards surgical tray rationalisation in inguinoscrotal day case surgery in the republic of Ireland.

INTRODUCTION: Lean methodologies have been used successfully in both industry and healthcare to reduce waste. The operating room (OR) and central supplies department (CSD) are areas associated with high hospital costs. The aim of this study was to employ Lean methodologies to support the rationalisation of surgical trays in paediatric inguinoscrotal surgery in order to reduce instrument wastage, processing times and overall costs in a European setting. METHODS: This was a prospective, pilot observation and implementation study using Lean methodology including DMAIC (Define, Measure, Analyse, Improve and Control) cycles. Relevant tray set-up included trays for boys ≥12 months age undergoing open elective inguinoscrotal surgery. A comparative analysis of two phases, pre and post-standardization was then carried out with respect to operating times, instrument set-up times, tray weights, and costs. Instruments that were used <40% of the time were eliminated from the surgical tray. RESULTS: Rationalization of the inguinoscrotal tray led to a 34.7% reduction in tray size, with a concomitant time-reduction of >2 min per case. The average overall instrument utilisation rate increased from 56% to 80% across users. Cost savings were projected at €5380.40 per annum based on current changes. There were no differences in operative time, or adverse outcomes. DISCUSSION: At the hospital level, the reduction in variation, and rationalisation of this single surgical tray could lead to both operational (Tray assembly process; Operating rooms; Ergonomic functionality) as well as economic (Sterilisation; Instrument repair; Purchases) financial and ergonomic improvements for the healthcare system. The reduction in time taken to count and sterilise instruments can lead to a potential manpower saving involving a redistribution of activities to other areas which may require them. CONCLUSION: Surgical tray rationalisation is emerging Lean concept with overlap across a number of specialities, and represents a technique by which to manage costs, and improve supply chain efficiency without any adverse effect in patient healthcare outcomes.