On real-valued SDE and nonnegative-valued SDE population models with demographic variability.

Population dynamics with demographic variability is frequently studied using discrete random variables with continuous-time Markov chain (CTMC) models. An approximation of a CTMC model using continuous random variables can be derived in a straightforward manner by applying standard methods based on the reaction rates in the CTMC model. This leads to a system of Itô stochastic differential equations (SDEs) which generally have the form [Formula: see text] where [Formula: see text] is the population vector of random variables, [Formula: see text] is the drift vector, and G is the diffusion matrix. In some problems, the derived SDE model may not have real-valued or nonnegative solutions for all time. For such problems, the SDE model may be declared infeasible. In this investigation, new systems of SDEs are derived with real-valued solutions and with nonnegative solutions. To derive real-valued SDE models, reaction rates are assumed to be nonnegative for all time with negative reaction rates assigned probability zero. This biologically realistic assumption leads to the derivation of real-valued SDE population models. However, small but negative values may still arise for a real-valued SDE model. This is due to the magnitudes of certain problem-dependent diffusion coefficients when population sizes are near zero. A slight modification of the diffusion coefficients when population sizes are near zero ensures that a real-valued SDE model has a nonnegative solution, yet maintains the integrity of the SDE model when sizes are not near zero. Several population dynamic problems are examined to illustrate the methodology.

Systems based analysis of human embryos and gene networks involved in cell lineage allocation.

BACKGROUND: Little is understood of the molecular mechanisms involved in the earliest cell fate decision in human development, leading to the establishment of the trophectoderm (TE) and inner cell mass (ICM) stem cell population. Notably, there is a lack of understanding of how transcriptional networks arise during reorganisation of the embryonic genome post-fertilisation. RESULTS: We identified a hierarchical structure of preimplantation gene network modules around the time of embryonic genome activation (EGA). Using network models along with eukaryotic initiation factor (EIF) and epigenetic-associated gene expression we defined two sets of blastomeres that exhibited diverging tendencies towards ICM or TE. Analysis of the developmental networks demonstrated stage specific EIF expression and revealed that histone modifications may be an important epigenetic regulatory mechanism in preimplantation human embryos. Comparison to published RNAseq data confirmed that during EGA the individual 8-cell blastomeres are transcriptionally primed for the first lineage decision in development towards ICM or TE. CONCLUSIONS: Using multiple systems biology approaches to compare developmental stages in the early human embryo with single cell transcript data from blastomeres, we have shown that blastomeres considered to be totipotent are not transcriptionally equivalent. Furthermore we have linked the developmental interactome to individual blastomeres and to later cell lineage. This has clinical implications for understanding the impact of fertility treatments and developmental programming of long term health.

Long term use of hydraulic artificial urethral sphincters in nine dogs from New Zealand with urethral sphincter mechanism incompetence.

AIMS: To report on the long-term outcomes of hydraulic artificial urethral sphincter (HAUS) placement for the correction of urethral sphincter mechanism incompetence (USMI) in New Zealand dogs. METHODS: Retrospective data were obtained from cases of dogs which had a HAUS placed after failed medical and/or surgical management of USMI between August 2012 and November 2016. Owner assessment of urinary incontinence was evaluated by an online survey in May 2017 using a visual analogue scale (0 being normal, 100 being severely affected) for the frequency, volume and severity of any straining to urinate, immediately prior to the placement of the HAUS and at the time of the survey. The number of days between surgery and the completion of survey were recorded. RESULTS: Seven females and two male dogs, which were all desexed except for one female, were eligible for inclusion in the study. The period of follow-up following HAUS placement ranged from 206-1,685 days. Following HAUS placement, frequency and volume of urinary incontinence decreased for six dogs and were practically unchanged for three dogs. The median frequency score decreased from 70 to 13 and the volume score decreased from 73 to 12. There was no consistent change in the perceived degree of straining to urinate. Complications occurred in three dogs; one required repositioning of a dislodged injection port, one required management for haematuria and a hypoplastic bladder, and one required surgical removal of fibrous tissue around the HAUS cuff. CONCLUSIONS AND CLINICAL RELEVENCE: HAUS placement was an effective method for the treatment of persistent USMI in most dogs and provided good clinical results based on owner assessment. The technique was associated with few complications and allowed successful long-term control of urinary incontinence without the need for medical management.

Nuclear quantum effect with pure anharmonicity and the anomalous thermal expansion of silicon.

Despite the widespread use of silicon in modern technology, its peculiar thermal expansion is not well understood. Adapting harmonic phonons to the specific volume at temperature, the quasiharmonic approximation, has become accepted for simulating the thermal expansion, but has given ambiguous interpretations for microscopic mechanisms. To test atomistic mechanisms, we performed inelastic neutron scattering experiments from 100 K to 1,500 K on a single crystal of silicon to measure the changes in phonon frequencies. Our state-of-the-art ab initio calculations, which fully account for phonon anharmonicity and nuclear quantum effects, reproduced the measured shifts of individual phonons with temperature, whereas quasiharmonic shifts were mostly of the wrong sign. Surprisingly, the accepted quasiharmonic model was found to predict the thermal expansion owing to a large cancellation of contributions from individual phonons.

Design and operating characteristic of a vacuum furnace for time-of-flight inelastic neutron scattering measurements.

We present the design and operating characteristics of a vacuum furnace used for inelastic neutron scattering experiments on a time-of-flight chopper spectrometer. The device is an actively water cooled radiant heating furnace capable of performing experiments up to 1873 K. Inelastic neutron scattering studies performed with this furnace include studies of phonon dynamics and metallic liquids. We describe the design, control, characterization, and limitations of the equipment. Further, we provide comparisons of the neutron performance of our device with commercially available options. Finally we consider upgrade paths to improve performance and reliability.

Maxillary unicystic ameloblastoma in a 6-week-old filly evaluated with computed tomography.

CASE REPORT: A 6-week-old Thoroughbred filly was presented for evaluation of an expansile mass overlying the right nasal passage and causing respiratory stertor. On skull radiographs, there was a loculated, soft tissue-opaque mass identified dorsal to the right upper premolars and effacing the right nasal cavity. Computed tomography (CT) revealed a locally extensive mass with relatively benign characteristics located centrally on the tooth root apices of the deciduous second premolar (506). The mass extended axially into the right nasal cavity, occluding the meatuses and causing displacement of the nasal septum to the left. CLINICAL OUTCOME & SIGNIFICANCE: Surgical excision was not deemed feasible with an athletic future in mind and the owners elected to euthanase the filly. Histopathologically, the mass was consistent with unicystic ameloblastoma and was lined intermittently with palisading, columnar basal cells (ameloblast-like cells) overlying a zone containing stellate cells in loose stroma. To the authors' knowledge this is the first report of a CT scan of an equine ameloblastoma. Although histopathology was essential for definitive diagnosis, CT clearly defined the origin of the mass and identified its locally extensive, cystic nature, which enabled informed decisions to be made.

Prevention of allograft HCV recurrence with peri-transplant human monoclonal antibody MBL-HCV1 combined with a single oral direct-acting antiviral: A proof-of-concept study.

Patients with active hepatitis C virus (HCV) infection at transplantation experience rapid allograft infection, increased risk of graft failure and accelerated fibrosis. MBL-HCV1, a neutralizing human monoclonal antibody (mAb) targeting the HCV envelope, was combined with a licensed oral direct-acting antiviral (DAA) to prevent HCV recurrence post-transplant in an open-label exploratory efficacy trial. Eight subjects received MBL-HCV1 beginning on the day of transplant with telaprevir initiated between days 3 and 7 post-transplantation. Following FDA approval of sofosbuvir, two subjects received MBL-HCV1 starting on the day of transplant with sofosbuvir initiated on day 3. Combination treatment was administered for 8-12 weeks or until the stopping rule for viral rebound was met. The primary endpoint was undetectable HCV RNA at day 56 with exploratory endpoints of sustained virologic response (SVR) at 12 and 24 weeks post-treatment. Both subjects receiving mAb and sofosbuvir achieved SVR24. Four of eight subjects in the mAb and telaprevir group met the primary endpoint; one subject achieved SVR24 and three subjects relapsed 2-12 weeks post-treatment. The other four subjects experienced viral breakthrough. There were no serious adverse events related to study treatment. This proof-of-concept study demonstrates that peri-transplant immunoprophylaxis combined with a single oral direct-acting antiviral in the immediate post-transplant period can prevent HCV recurrence.

Human monoclonal antibody MBL-HCV1 delays HCV viral rebound following liver transplantation: a randomized controlled study.

Rapid allograft infection complicates liver transplantation (LT) in patients with hepatitis C virus (HCV). Pegylated interferon-α and ribavirin therapy after LT has significant toxicity and limited efficacy. The effect of a human monoclonal antibody targeting the HCV E2 glycoprotein (MBL-HCV1) on viral clearance was examined in a randomized, double-blind, placebo-controlled pilot study in patients infected with HCV genotype 1a undergoing LT. Subjects received 11 infusions of 50 mg/kg MBL-HCV1 (n=6) or placebo (n=5) intravenously with three infusions on day of transplant, a single infusion on days 1 through 7 and one infusion on day 14 after LT. MBL-HCV1 was well-tolerated and reduced viral load for a period ranging from 7 to 28 days. Median change in viral load (log10 IU/mL) from baseline was significantly greater (p=0.02) for the antibody-treated group (range -3.07 to -3.34) compared to placebo group (range -0.331 to -1.01) on days 3 through 6 posttransplant. MBL-HCV1 treatment significantly delayed median time to viral rebound compared to placebo treatment (18.7 days vs. 2.4 days, p<0.001). As with other HCV monotherapies, antibody-treated subjects had resistance-associated variants at the time of viral rebound. A combination study of MBL-HCV1 with a direct-acting antiviral is underway.

Retention of drug administration skills after intensive teaching.

We have identified deficiencies in medical students' drug administration skills, and we attempted to address them with interactive online teaching modules and simulated critical incident scenarios. Short-term improvements have been evident with this intensive effort, but medium-term retention of skills has not been measured. A drug administration lecture, an online module and a simulated emergency scenario were offered to final year clinical students. None of the teaching was compulsory but participation was recorded, along with students' simulator performances and marks in an objective structured practical examination 9 months later. A poor simulator score predicted a poor performance in the later examination. Participation in the simulated scenario only significantly improved examination scores when supplemented by online teaching (p = 0.002). Intensive drug administration teaching using an online module and high fidelity simulation improves drug administration skills in the medium term. Students found simulation much more engaging than online teaching.

Failed tracheostomy under local anaesthesia...plan B?

Severe stridor of recent onset is a challenge to deal with because of the lack of investigations on which to base the management plan. We describe a case of an elderly lady who presented to us with a short history of severe stridor. We encountered unanticipated difficulties with tracheostomy under local anaesthesia as the thyroid was replaced by a diffuse mass and the airway had to be secured by an awake fibre-optic intubation. Awake fibre-optic intubation is thought to be a relative contraindication in acute upper airway obstruction, but occasionally tracheostomy under local anaesthesia may not be possible and in experienced hands an awake fibre-optic intubation is a reasonable alternative.

The discrete dynamics of monotonically decomposable maps.

We extend results of Gouzé and Hadeler (in Nonlinear World 1:23-34, 1994) concerning the dynamics generated by a map on an ordered metric space that can be decomposed into increasing and decreasing parts. Our main results provide sufficient conditions for the existence of a globally asymptotically stable fixed point for the map. Applications to discrete-time, stage-structured population models are given.

Awake insertion of the laryngeal mask airway using topical lidocaine and intravenous remifentanil.

We assessed the use of intravenous remifentanil for the insertion of the laryngeal mask airway in 10 healthy awake volunteers, a technique primarily developed to facilitate functional magnetic resonance imaging studies of anaesthesia. Each volunteer received 200 microg glycopyrronium intravenously. Topical airway anaesthesia was effected by 4 ml nebulised lidocaine 4%, followed by 12 sprays of lidocaine 10%. Remifentanil was subsequently infused to achieve an initial target effect-site concentration of 2 ng.ml(-1); increments of 1 ng.ml(-1) were allowed with the maximum effect-site concentration limited to 6 ng.ml(-1). Insertion of the laryngeal mask airway was successful on the first attempt in all cases. The median (IQR [range]) target effect-site remifentanil concentration at insertion was 2.5 (2-3 [2-4]) ng.ml(-1). All volunteers were co-operative during the procedure and only one reported discomfort. Sore throat was a complication in all volunteers. We conclude that the technique allows successful insertion of the laryngeal mask airway in healthy awake volunteers under conditions that were safe and reproducible.

Influence of improved teaching on medical students' acquisition and retention of drug administration skills.

BACKGROUND: Drug administration error is a major problem causing substantial morbidity and mortality worldwide. Lack of education about drug administration appears to be a causative factor. We devised an online teaching module for medical students and assessed its short- and long-term efficacy. METHODS: One hundred and thirty clinical medical students were invited to undertake additional, online, teaching about drug administration. Those participating were identified and the number of web pages viewed recorded. The students' knowledge retention was tested by means of drug administration questions incorporated into routine assessments and examinations over the next 6 months. Other indices of all students' performance were recorded to correct for confounding factors. RESULTS: Just over half (52%) responded to the invitation to participate. The amount of interest they showed in the teaching module correlated positively with their performance in questions about drug administration, although the latter waned over time. Surprisingly, correcting for students' general ability and keenness revealed that the less able students were most likely to undertake the teaching module. CONCLUSIONS: Additional online teaching about drug administration improves students' knowledge of the topic but clearly requires reinforcement; however, only about half the students took up the option. Medical students must acquire these fundamental skills, and online teaching can help. Medical educators must ensure that drug administration is taught formally to all students as part of the curriculum and must understand that it may require additional teaching.

Emergency tracheal catheterization for jet ventilation: a role for the ENT surgeon?

Stridor causing respiratory failure is an ENT and anaesthetic emergency requiring prompt management to secure a clear airway. We describe a case of subacute partial upper airway obstruction due to a large laryngeal carcinoma in an 81-year-old male resulting in respiratory failure. The patient became apnoeic after gaseous induction of general anaesthesia, and after two failed intubation attempts an emergency transtracheal airway catheter was placed by the surgeon under direct vision below the cricothyroid membrane, as this had tumour involvement. The patient was subsequently manually jet-ventilated with ease until a formal tracheostomy was made. Where difficulties with tracheal anatomy are encountered due to the presence of pathology, the insertion of a temporary airway catheter for jet ventilation by the surgeon can buy valuable time and be life-saving.

Integrated approaches to academic anaesthesia - the Cambridge experience.

There is mounting concern about the pressures experienced by University Departments of Anaesthesia, which, if lost, could threaten undergraduate peri-operative medicine teaching, development of critical appraisal skills among anaesthetists, and the future of coherent research programs. We have addressed these problems by establishing a foundation course in scientific methods and research techniques (the Cambridge SMART Course), complemented by competitive, fully funded, 12-month academic trainee attachments. Research conducted during academic attachments has been published and used to underpin substantive grant applications allowing work towards higher degrees. Following the attachment, a flexible scheme ensures safe reintroduction to clinical training. Research at consultant level is facilitated by encouraging applications for Clinician Scientist Fellowships, and by ensuring that the University Department champions, legitimises and validates the allocation of research time within the new consultant contract. We believe that these are important steps in safeguarding research and teaching in anaesthesia, critical care and peri-operative medicine.

A web-based system for teaching, assessment and examination of the undergraduate peri-operative medicine curriculum.

Today's students are generally computer literate and have high expectations of university information technology resources. Most United Kingdom medical schools now provide networked computers for learning, research, communication and accessing the worldwide web. We have exploited these advances to augment and improve the teaching of peri-operative medicine and anaesthesia to medical students in our university, who are taught in several hospitals over a wide geographical area. Course material such as departmental induction information, lecture notes and assessment sheets can be accessed online, contributing to the smooth running of the course. Streamed videos and simulations allow students to familiarise themselves with common practical procedures in advance. Development of a web-based end of course assessment has resulted in substantially less administration and bureaucracy for course organisers and proved to be a valuable research tool. Students' and teachers' opinions of the new course structure have been overwhelmingly positive.

Effect of videotape feedback on anaesthetists' performance while managing simulated anaesthetic crises: a multicentre study.

The aim of this study was to examine the performance of anaesthetists while managing simulated anaesthetic crises and to see whether their performance was improved by reviewing their own performances recorded on videotape. Thirty-two subjects from four hospitals were allocated randomly to one of two groups, with each subject completing five simulations in a single session. Individuals in the first group completed five simulations with only a short discussion between each simulation. Those in the second group were allowed to review their own performance on videotape between each of the simulations. Performance was measured by both 'time to solve the problem' and mental workload, using anaesthetic chart error as a secondary task. Those trainees exposed to videotape feedback had a shorter median 'time to solve' and a smaller decrease in chart error when compared to those not exposed to video feedback. However, the differences were not statistically significant, confirming the difficulties encountered by other groups in designing valid tests of the performance of anaesthetists.

Childhood obesity: a challenge for the anaesthetist?

The definition of childhood obesity has not been standardized in the past, making studies difficult to compare. In spite of this, the increase in the incidence of childhood obesity is evident and has now reached epidemic proportions. Obese children experience few of the medical complications seen in obese adults. Respiratory physiology appears to be most affected, the degree of which is determined by the level of obesity. Although there is a considerable amount of information on the anaesthetic management of the obese adult, very little has been written concerning the obese child. There is less pathology in the obese child when compared with the adult but some evidence shows a higher likelihood of a critical incident occurring when anaesthetizing such children. This shows that we need to be as worried about anaesthetizing the obese child as we are for the obese adult. This concern should increase with increasing body mass index.