Age and the anaesthetist: considerations for the individual anaesthetist and workforce planning: Guidelines about the ageing anaesthetic workforce from the Association of Anaesthetists: Guidelines for the ageing anaesthetic workforce from the Association of Anaesthetists.

There is clear evidence of a growing workforce gap and this is compounded by demographic data that show the current workforce is ageing. Within the current workforce, more doctors are taking voluntary early retirement and the loss of these experienced clinicians from departments can have wide-ranging effects. Older doctors are at risk of age-related health problems (e.g. sight, musculoskeletal, menopause) and are more susceptible to the effects of fatigue, which may increase the risk of error and or complaint. The purpose of this working party and advocacy campaign was to address concerns over the number of consultants retiring at the earliest opportunity and whether a different approach could extend the working career of consultant anaesthetists and SAS doctors. This could be viewed as 'pacing your career'. The earlier this is considered in a clinician's career the greater the potential mitigation on individuals.

Integument, mortality, and skeletal strength in extended production cycles for laying hens - effects of genotype and dietary zinc source.

1. This study on long-life layers, covering the period 20-100 weeks of age, investigated longitudinal effects on mortality, layer integument, and skeletal properties in Bovans White (BoW) and Lohmann Selected Leghorn Classic (LSL), with or without supplementation with dietary organic zinc (Zn).2. Two experiments, using 1440 layers in furnished small group cages (FC) and 1836 layers in a traditional floor housing system (Floor), were run in parallel. Each replicate consisted of five adjacent cages containing eight hens in each FC, or a pen with 102 layers in the Floor group.3. Mortality was recorded daily. Integument and keel bone condition were scored at 35, 55, 85, and 100 weeks of age on 20% of the layers. Tibial strength was recorded from 933 layers at 100 weeks. Statistical analyses were performed on replicate means, with four to five and nine replicates per combination of hybrid and diet in Floor and FC groups, respectively.4. Cumulative mortality was 9.6% and 16.3% in FC and Floor, respectively, and increased in the latter part of the production cycle, particularly in the Floor group.5. In FC, LSL had inferior feather cover, less keel bone deviation, and shorter claws than BoW. In Floor, LSL had superior feather cover, less severe vent wounds, more bumble foot, and cleaner plumage than BoW. In both production systems, claws grew longer and keel bone deviation became more severe with age.6. In FC, layers fed organic Zn had lower body weight and less keel bone deviation at 100 weeks of age.7. In conclusion, keel bone integrity, claw length, and mortality rate are potential threats to welfare in long-life layers. Feather pecking is a problem that needs addressing at an early stage in the production period. On the whole, organic Zn did not improve welfare conditions in long-life layers.

Comparative analysis of the morphology, chemistry and structure of the tibiotarsus, humerus and keel bones in laying hens.

1. Bone properties are adapted to their specific functions in the animal, so various types of bones develop different characteristics depending on their location in the skeleton.2. The aim of this research was to compare the chemical composition, mineral characteristics and structural organisation in tibiotarsus, humerus and keel bones as representatives of hen skeletal mineralisation. Complementary analytical techniques, such as X-ray radiography, optical and electron microscopy, thermogravimetry and 2D X-ray diffraction, were used for characterisation.3. The humerus had a thinner cortex and cortical bone mineral had higher crystallinity and a greater degree of crystal orientation than the tibiotarsus. The humerus generally lacks medullary bone although, when present, it has a higher mineral content than seen in the tibiotarsus. These differences were attributed to the different forces that stimulate bone formation and remodelling.4. The keel cortical bone had a lower degree of mineralisation than the tibiotarsus or humerus. Its degree of mineralisation decreased from the cranial to the distal end of the bone. This gradient may affect keel mechanical properties, making it more prone to deformation and fractures.5. Data from studying different bones in laying hens can help to understand mineralisation as well as finding solutions to prevent osteoporosis-related fractures.

Molecular engineering strategies and methods for the expression and purification of IgG1-based bispecific bivalent antibodies.

In recent years, bispecific antibodies (BisAbs) have emerged as novel pharmaceutical candidates owing to their ability to engage two disease mediators simultaneously, thus providing a possible alternative therapeutic approach in complex diseases such as cancer and inflammation. Here we provide an overview of the molecular design, recombinant expression in mammalian cells and purification of BisAbs based on full-length IgG-scFv formats. Practical considerations and strategies to optimize transient expression and purification are also discussed.

Influence of physical activity on tibial bone material properties in laying hens.

Laying hens develop a type of osteoporosis that arises from a loss of structural bone, resulting in high incidence of fractures. In this study, a comparison of bone material properties was made for lines of hens created by divergent selection to have high and low bone strength and housed in either individual cages, with restricted mobility, or in an aviary system, with opportunity for increased mobility. Improvement of bone biomechanics in the high line hens and in aviary housing was mainly due to increased bone mass, thicker cortical bone and more medullary bone. However, bone material properties such as cortical and medullary bone mineral composition and crystallinity as well as collagen maturity did not differ between lines. However, bone material properties of birds from the different type of housing were markedly different. The cortical bone in aviary birds had a lower degree of mineralization and bone mineral was less mature and less organized than in caged birds. These differences can be explained by increased bone turnover rates due to the higher physical activity of aviary birds that stimulates bone formation and bone remodeling. Multivariate statistical analyses shows that both cortical and medullary bone contribute to breaking strengthThe cortical thickness was the single most important contributor while its degree of mineralization and porosity had a smaller contribution. Bone properties had poorer correlations with mechanical properties in cage birds than in aviary birds presumably due to the greater number of structural defects of cortical bone in cage birds.

Size of common bile duct stones on MRCP predicts likelihood of positive findings at ERCP.

OBJECTIVE: To ascertain if direct measurement of the size of common bile duct stones (CBD) on magnetic resonance cholangio-pancreatography (MRCP) can be used to predict the likelihood of a positive endoscopic retrograde cholangio-pancreatography (ERCP) result. Should we be carrying out ERCPs on all patients with CBD stones? METHODS: We retrospectively analysed the records of 1812 consecutive patients undergoing MRCP between November 2009 and November 2014 at the Victoria Infirmary. A measurable CBD stone was present in 383 patients, of whom 293 successfully underwent ERCP. RESULTS: 221 patients (75%) had stones demonstrated on ERCP. A receiver operating curve (ROC) was plotted correlating stone size with the likelihood of a positive ERCP result, and demonstrates that using a cut off of >4 mm as an indication for ERCP gives the mathematical best-fit correlation with a sensitivity of 83% (95% CI 78-88) and specificity of 66% (95% CI 53-77). CONCLUSIONS: In our current practice, all patients with CBD stones at MRCP are considered for ERCP regardless of stone size. Our results would support the hypothesis that as size decreases the likelihood of spontaneous stone passage increases. Although the threshold of mathematical best compromise is >4 mm to minimise both type 1 and type 2 errors, we would favour a lower threshold of 2 mm above which ERCP is performed (sensitivity 98.65, 95% CI 96.1-99.7, specificity 25.71%, CI 16.0-37.6). For patients with stones measuring 2 mm or less, early operative intervention with intraoperative cholangiography to confirm duct clearance could be a suitable alternative.

A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors.

BACKGROUND: Focal adhesion kinase (FAK) is important in cancer growth, survival, invasion, and migration. The purpose of this study was to determine the maximum tolerated dose (MTD), safety, pharmacokinetics (PK), and pharmacodynamics (PD) of the FAK inhibitor, GSK2256098, in cancer patients. PATIENTS AND METHODS: The dose of GSK2256098 was escalated, in cohorts of patients with advanced cancer, from 80 to 1500 mg, oral twice daily (BID), until the MTD was determined. Serial blood samples were obtained from all patients, and the PK was determined. Paired tumor biopsies were obtained in select patients, and the level of phospho-FAK (pFAK) was determined. RESULTS: Sixty-two patients (39 males, 23 females; median age 61 y.o., range 21-84) received GSK2256098. Dose-limiting toxicities of grade 2 proteinuria (1000 mg BID), grade 2 fatigue, nausea, vomiting (1250 mg BID), and grade 3 asthenia and grade 2 fatigue (1500 mg BID) were reported with the MTD identified as 1000 mg BID. The most frequent adverse events (AEs) were nausea (76%), diarrhea (65%), vomiting (58%), and decreased appetite (47%) with the majority of AEs being grades 1-2. The PK was generally dose proportional with a geometric mean elimination half-life range of 4-9 h. At the 750, 1000, and 1500 mg BID dose levels evaluated, the pFAK, Y397 autophosphorylation site, was reduced by ∼80% from baseline. Minor responses were observed in a patient with melanoma (-26%) and three patients with mesothelioma (-13%, -15%, and -17%). In the 29 patients with recurrent mesothelioma, the median progression-free survival was 12 weeks with 95% CI 9.1, 23.4 weeks (23.4 weeks merlin negative, n = 14; 11.4 weeks merlin positive, n = 9; 10.9 weeks merlin status unknown, n = 6). CONCLUSIONS: GSK2256098 has an acceptable safety profile, has evidence of target engagement at doses at or below the MTD, and has clinical activity in patients with mesothelioma, particularly those with merlin loss.

Brugia malayi infective larvae fail to activate Langerhans cells and dermal dendritic cells in human skin.

Filarial infection in humans is initiated when a mosquito deposits third-stage parasite larvae (L3) in the skin. Langerhans cells (LCs) and dermal dendritic cells (DDCs) are the first cells that the parasite encounters, and L3s must evade these highly effective antigen-presenting cells to establish infection. To assess LC and DDC responses to L3 in human skin, we employed three models of increasing physiologic relevance: in vitro-generated LCs, epidermal blister explants and full-thickness human skin sections. In vitro-generated LCs expressed TLR1-10 and robustly produced IL-6 and TNF-α in response to PolyI:C, but pre-exposure to L3s did not alter inflammatory cytokine production or TLR expression. L3s did not modulate expression of LC markers CDH1, CD207, or CD1a, or the regulatory products TSLP or IDO in epidermal explants or in vitro-generated LC. LC, CD14+ DDC, CD1c+ DC and CD141+ DC from human skin sections were analysed by flow cytometry. While PolyI:C potently induced CCL22 production in LC, CD1c+ DC, and CD141+ DC, and IL-10 production in LC, L3s did not modulate the numbers of or cytokine production by any skin DC subset. L3s broadly failed to activate or modulate LCs or DDCs, suggesting filarial larvae expertly evade APC detection in human skin.

Exploring the recovery and detection of messenger RNA and DNA from enhanced fingermarks in blood.

Often in the examination of bloodstained fingermarks discussion occurs around whether to prioritise the fingerprint evidence or focus on the biological evidence. Collecting a sample for genetic profiling may result in the loss of ridge detail that could have been used for fingerprint comparison. Fingermark enhancement and recovery methods along with sample collection methods could also compromise downstream genetic analysis. Previous forensic casework has highlighted circumstances where, after enhancement had been performed, it would have been extremely valuable to both identify the body fluid and generate a DNA profile from the same sample. We enhanced depletion series of fingermarks made in blood, using single treatments consisting of aqueous amido black, methanol-based amido black, acid yellow and leucocrystal violet, and exposure to long wave UV light. We then extracted the DNA and RNA for profiling, to assess the recovery and detection of genetic material from the enhanced fingermarks. We have shown that genetic profiling of bloodstained fingermarks can be successful after chemical enhancement; however it may still be necessary to prioritise evidence types in certain circumstances. From our results it appears that even with visible bloodstained fingermarks, leucocrystal violet can reduce the effectiveness of subsequent messenger RNA profiling. Aqueous amido black and acid yellow also have adverse effects on messenger RNA profiling of depleted fingermarks with low levels of cellular material. These results help with forensic decision-making by expanding knowledge of the extent of the detrimental effects of blood-enhancement reagents on both DNA profiling and body fluid identification using messenger RNA profiling.

Can anti-Müllerian hormone concentrations be used to determine gonadotrophin dose and treatment protocol for ovarian stimulation?

The ability to predict the response potential of women to ovarian stimulation may allow the development of individualized ovarian stimulation protocols. This tailored approach to ovarian stimulation could reduce the incidence of ovarian hyperstimulation syndrome in women predicted to have an excessive response to stimulation or could improve pregnancy outcomes in women classed as poor responders. Namely, variation of the type of gonadotrophin-releasing hormone (GnRH) analogue or the form and dosage of gonadotrophin used for stimulation could be adjusted according to an individual's response potential. The serum concentration of anti-Müllerian hormone (AMH) is established as a reliable marker of ovarian reserve, with decreasing concentrations correlated with reduced response potential. This review examines the current evidence evaluating individualized ovarian stimulation protocols using AMH concentration as a predictive marker of ovarian response. The rationale behind why specific treatment protocols based on individual response potential may be more suitable is also discussed. Based on current evidence, it appears that the use of AMH serum concentrations to predict ovarian response and optimize treatment strategies is a promising approach for improving pregnancy outcomes in women undergoing ovarian stimulation. However, prospective randomized controlled trials evaluating this approach are needed before any firm conclusions can be drawn.

Is body mass index a useful measure of excess body fatness in adolescents and young adults with Down syndrome?

BACKGROUND: To determine the validity of body mass index (BMI) to identify excess fatness in youth with Down syndrome (DS). METHODS: Using the Centers for Disease Control and Prevention (CDC) growth reference, we defined overweight (≥ 85th percentile) and obesity (≥ 95th percentile) based on participants' age- and sex-specific BMI z-scores, calculated from measured height and weight. Percentage body fat was measured by dual-energy X-ray absorptiometry. We determined sensitivity, specificity, positive predictive value, negative predictive value and efficiency of BMI percentiles to identify excess adiposity relative to elevated percentage body fat cut-offs developed from the Pediatric Rosetta Body Composition project in 32 youth (20 boys/12 girls), ages 13-21 years with Down syndrome. RESULTS: For adolescents with Down syndrome using the cut-off points of 95th percentile for BMI (obesity), sensitivity and specificity were 71% and 96% respectively. Positive predictive value was 83% and negative predictive value was 92%. Overall efficiency was 91%. Sensitivity and specificity for BMI cut-offs above the 85th percentile (overweight) were 100% and 60% respectively. The positive predictive value was 41% and negative predictive value was 100%. Overall efficiency was 69%. CONCLUSION: On the whole, the obesity (≥ 95th percentile) cut-off performs better than the overweight cut-off (85th-94th percentile) in identifying elevated fatness in youth with DS.

Quantitative assignment of reaction directionality in a multicompartmental human metabolic reconstruction.

Reaction directionality is a key constraint in the modeling of genome-scale metabolic networks. We thermodynamically constrained reaction directionality in a multicompartmental genome-scale model of human metabolism, Recon 1, by calculating, in vivo, standard transformed reaction Gibbs energy as a function of compartment-specific pH, electrical potential, and ionic strength. We show that compartmental pH is an important determinant of thermodynamically determined reaction directionality. The effects of pH on transport reaction thermodynamics are only seen to their full extent when metabolites are represented as pseudoisomer groups of multiple protonated species. We accurately predict the irreversibility of 387 reactions, with detailed propagation of uncertainty in input data, and manually curate the literature to resolve conflicting directionality assignments. In at least half of all cases, a prediction of a reversible reaction directionality is due to the paucity of compartment-specific quantitative metabolomic data, with remaining cases due to uncertainty in estimation of standard reaction Gibbs energy. This study points to the pressing need for 1), quantitative metabolomic data, and 2), experimental measurement of thermochemical properties for human metabolites.

Mass conserved elementary kinetics is sufficient for the existence of a non-equilibrium steady state concentration.

Living systems are forced away from thermodynamic equilibrium by exchange of mass and energy with their environment. In order to model a biochemical reaction network in a non-equilibrium state one requires a mathematical formulation to mimic this forcing. We provide a general formulation to force an arbitrary large kinetic model in a manner that is still consistent with the existence of a non-equilibrium steady state. We can guarantee the existence of a non-equilibrium steady state assuming only two conditions; that every reaction is mass balanced and that continuous kinetic reaction rate laws never lead to a negative molecule concentration. These conditions can be verified in polynomial time and are flexible enough to permit one to force a system away from equilibrium. With expository biochemical examples we show how reversible, mass balanced perpetual reaction(s), with thermodynamically infeasible kinetic parameters, can be used to perpetually force various kinetic models in a manner consistent with the existence of a steady state. Easily testable existence conditions are foundational for efforts to reliably compute non-equilibrium steady states in genome-scale biochemical kinetic models.

A variational principle for computing nonequilibrium fluxes and potentials in genome-scale biochemical networks.

We derive a convex optimization problem on a steady-state nonequilibrium network of biochemical reactions, with the property that energy conservation and the second law of thermodynamics both hold at the problem solution. This suggests a new variational principle for biochemical networks that can be implemented in a computationally tractable manner. We derive the Lagrange dual of the optimization problem and use strong duality to demonstrate that a biochemical analogue of Tellegen's theorem holds at optimality. Each optimal flux is dependent on a free parameter that we relate to an elementary kinetic parameter when mass action kinetics is assumed.

The Impact of a Multimodal Sport Science-Based Prehabilitation Program on Clinical Outcomes in Abdominal Cancer Patients: A Cohort Study.

BACKGROUND: The potential for prehabilitation programs to impact clinical outcomes is uncertain in abdominal cancer patients due to the short window of time to intervene and the weakened state of the patients. To improve the effectiveness of prehabilitation intervention, a multimodal sports science approach was implemented. METHODS: Prior to cancer-related surgery, 21 patients participated in a 4-week exercise and nutrition prehabilitation program comprised of blood flow restriction exercise (BFR) and a sports nutrition supplement. Retrospective data of 71 abdominal cancer patients who underwent usual preoperative care was used as a comparator control group (CON). At 90 days post-surgery, clinical outcomes were quantified. RESULTS: Prehabilitation was associated with a shorter length of hospital stay (P = .02) with 5.5 fewer days (4.7 ± 2.1 vs 10.2 ± 1.2 days in CON) and decreased incidence of any complications (P = .03). Prehabilitation was not related to incidence of serious complications (P = .17) or readmission rate (P = .59). The prehabilitation group recorded 58% more steps on day 5 after surgery (P = .043). DISCUSSION: A 4-week home-based prehabilitation program composed of BFR training and sports nutrition supplementation was effective in reducing postoperative complications and length of hospital stay in older patients with abdominal cancer.ClinicalTrials.gov Identifier: NCT04073381.

External validation of nomogram for the decline in serum anti-Müllerian hormone in women: a population study of 15,834 infertility patients.

The value of anti-müllerian hormone (AMH) as a marker of the ovarian reserve is becoming clear in a range of clinical contexts.This study reports the external validation of a quadratic model-based AMH­age nomogram using a cohort of 15,834 US women. All models previously investigated for the decline in ovarian reserve (i.e. linear, bi-linear, decay curve, power and quadratic models) tended to overestimate AMH by approximately 11% versus the published nomogram, indicating some between-population heterogeneity. Bootstrapping of 1000 datasets indicated that the quadratic model provided the best fit, confirming the choice of this model in the AMH­age nomogram. This nomogram can therefore be used with confidence for the interpretation of AMH in clinical populations.

The inflammatory response in lungs of rats exposed on the airborne particles collected during different seasons in four European cities.

Epidemiological studies have reported associations of ambient particulate air pollution, especially particulate matter (PM) less than 10 µm with exacerbations of asthma and chronic obstructive pulmonary disease. In an in vivo model, we have tested the toxicity of urban airborne particles collected during spring, summer, and winter seasons in four cities (Amsterdam, Lodz, Oslo, and Rome) spread across Europe. The seasonal differences in inflammatory responses were striking, and almost all the study parameters were affected by PM. Coarse fractions of the urban particle samples were less potent per unit mass than the fine fractions in increasing cytokine [macrophage inflammatory protein (MIP)-2 and tumor necrosis factor (TNF)-α] levels and in reducing Clara-cell secretory protein (CC16) levels. This study shows that PM collected at 4 contrasting sites across Europe and during different seasons have differences in toxic potency. These differences were even more prominent between the fine and coarse fractions of the PM.

A Mobile App With Multimodality Prehabilitation Programs for Patients Awaiting Elective Surgery: Development and Usability Study.

BACKGROUND: Complying with a prehabilitation program is difficult for patients who will undergo surgery, owing to transportation challenges and a limited intervention time window. Mobile health (mHealth) using smartphone apps has the potential to remove barriers and improve the effectiveness of prehabilitation. OBJECTIVE: This study aimed to develop a mobile app as a tool for facilitating a multidisciplinary prehabilitation protocol involving blood flow restriction training and sport nutrition supplementation. METHODS: The app was developed using "Appy Pie," a noncoding app development platform. The development process included three stages: (1) determination of principles and requirements of the app through prehabilitation research team meetings; (2) app prototype design using the Appy Pie platform; and (3) app evaluation by clinicians and exercise and fitness specialists, technical professionals from Appy Pie, and non-team-member users. RESULTS: We developed a prototype of the app with the core focus on a multidisciplinary prehabilitation program with accessory features to improve engagement and adherence to the mHealth intervention as well as research-focused features to evaluate the effects of the program on frailty status, health-related quality of life, and anxiety level among patients awaiting elective surgery. Evaluations by research members and random users (n=8) were consistently positive. CONCLUSIONS: This mobile app has great potential for improving and evaluating the effectiveness of the multidisciplinary prehabilitation intervention in the format of mHealth in future.