Modelling red blood cell optical trapping by machine learning improved geometrical optics calculations.

Optically trapping red blood cells allows for the exploration of their biophysical properties, which are affected in many diseases. However, because of their nonspherical shape, the numerical calculation of the optical forces is slow, limiting the range of situations that can be explored. Here we train a neural network that improves both the accuracy and the speed of the calculation and we employ it to simulate the motion of a red blood cell under different beam configurations. We found that by fixing two beams and controlling the position of a third, it is possible to control the tilting of the cell. We anticipate this work to be a promising approach to study the trapping of complex shaped and inhomogeneous biological materials, where the possible photodamage imposes restrictions in the beam power.

Influence of slow light effect on trapping force in optical tweezers.

We investigate the optical trapping of polystyrene microspheres in optical tweezers. The transverse capture gradient forces of polystyrene microspheres with different numerical aperture are theoretically and experimentally evaluated by the power spectral density roll-off method. It is found that the trapping force of the experimental measurement is much stronger than that of the theoretical results. The discordance is attributed to the slow light effect near the focus, which has been found in recent years [Science347, 857 (2015)10.1126/science.aaa3035; Opt. Express18, 10822 (2010)10.1364/OE.18.010822; Opt. Commun.332, 164 (2014)10.1016/j.optcom.2014.06.057]. The modified trapping force of the theoretical results by considering the slow light effect near the focus is well consistent with that of the experimental results.

Mutant clones in normal epithelium outcompete and eliminate emerging tumours.

Human epithelial tissues accumulate cancer-driver mutations with age1-9, yet tumour formation remains rare. The positive selection of these mutations suggests that they alter the behaviour and fitness of proliferating cells10-12. Thus, normal adult tissues become a patchwork of mutant clones competing for space and survival, with the fittest clones expanding by eliminating their less competitive neighbours11-14. However, little is known about how such dynamic competition in normal epithelia influences early tumorigenesis. Here we show that the majority of newly formed oesophageal tumours are eliminated through competition with mutant clones in the adjacent normal epithelium. We followed the fate of nascent, microscopic, pre-malignant tumours in a mouse model of oesophageal carcinogenesis and found that most were rapidly lost with no indication of tumour cell death, decreased proliferation or an anti-tumour immune response. However, deep sequencing of ten-day-old and one-year-old tumours showed evidence of selection on the surviving neoplasms. Induction of highly competitive clones in transgenic mice increased early tumour removal, whereas pharmacological inhibition of clonal competition reduced tumour loss. These results support a model in which survival of early neoplasms depends on their competitive fitness relative to that of mutant clones in the surrounding normal tissue. Mutant clones in normal epithelium have an unexpected anti-tumorigenic role in purging early tumours through cell competition, thereby preserving tissue integrity.

New approaches to pharmacosurveillance for monitoring prescription frequency, diversity, and co-prescription in a large sentinel network of companion animal veterinary practices in the United Kingdom, 2014-2016.

Pharmaceutical agents (PAs) are commonly prescribed in companion animal practice in the United Kingdom. However, little is known about PA prescription on a population-level, particularly with respect to PAs authorised for human use alone prescribed via the veterinary cascade; this raises important questions regarding the efficacy and safety of PAs prescribed to companion animals. This study explored new approaches for describing PA prescription, diversity and co-prescription in dogs, cats and rabbits utilising electronic health records (EHRs) from a sentinel network of 457 companion animal-treating veterinary sites throughout the UK over a 2-year period (2014-2016). A novel text mining-based identification and classification methodology was utilised to semi-automatically map practitioner-defined product descriptions recorded in 918,333 EHRs from 413,870 dogs encompassing 1,242,270 prescriptions; 352,730 EHRs from 200,541 cats encompassing 491,554 prescriptions, and 22,526 EHRS from 13,398 rabbits encompassing 18,490 prescriptions respectively. PA prescription as a percentage of booked consultations was 65.4% (95% confidence interval, CI, 64.6-66.3) in dogs; in cats it was 69.1% (95% CI, 67.9-70.2) and in rabbits, 56.3% (95% CI, 54.7-57.8). Vaccines were the most commonly prescribed PAs in all three species, with antibiotics, antimycotics, and parasiticides also commonly prescribed. PA prescription utilising products authorised for human use only (hence, 'human-authorised') comprised 5.1% (95% CI, 4.7-5.5) of total canine prescription events; in cats it was 2.8% (95% CI, 2.6-3.0), and in rabbits, 7.8% (95% CI, 6.5-9.0). The most commonly prescribed human-authorised PA in dogs was metronidazole (antibiotic); in cats and rabbits it was ranitidine (H2 histamine receptor antagonist). Using a new approach utilising the Simpson's Diversity Index (an ecological measure of relative animal, plant etc. species abundance), we identified differences in prescription based on presenting complaint and species, with rabbits generally exposed to a less diverse range of PAs than dogs or cats, potentially reflecting the paucity of authorised PAs for use in rabbits. Finally, through a novel application of network analysis, we demonstrated the existence of three major co-prescription groups (preventive health; treatment of disease, and euthanasia); a trend commonly observed in practice. This study represents the first time PA prescription has been described across all pharmaceutical families in a large population of companion animals, encompassing PAs authorised for both veterinary and human-only use. These data form a baseline against which future studies could be compared, and provides some useful tools for understanding PA comparative efficacy and risks when prescribed in the varied setting of clinical practice.

Alirocumab safety in people with and without diabetes mellitus: pooled data from 14 ODYSSEY trials.

AIM: To evaluate the safety of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab according to diabetes mellitus status. METHODS: Safety data from 14 trials (8-104-week durations) were analysed by treatment (alirocumab or placebo/ezetimibe control) and diabetes status (yes/no, defined by medical history). Adverse event data were assessed using descriptive statistics and Cox models. RESULTS: Of the 5234 trial participants, 1554 (29.7%) had diabetes. Overall, treatment-emergent adverse events were similar in the alirocumab and control groups, except for more frequent local injection site reactions with alirocumab. Fewer people with diabetes experienced local injection site reactions [alirocumab, 3.5%, control, 2.9%; hazard ratio 1.24 (95% CI 0.68-2.25)] than those without diabetes [alirocumab, 7.5%; control, 4.9%; hazard ratio 1.51 (95% CI 1.13-2.01)]. Those with diabetes reported a greater number of serious adverse events (alirocumab, 19.4%; control, 19.7%) than those without diabetes (alirocumab, 14.5%; control, 13.5%). In people with diabetes, major adverse cardiac events occurred in 2.7% of alirocumab-treated people [control, 3.3%; hazard ratio 0.74 (95% CI 0.41-1.35)]; in those without diabetes, 1.8% of alirocumab-treated people had major adverse cardiac events [control, 1.7%; hazard ratio 0.95 (95% CI 0.56-1.62)]. Overall, no increase in HbA1c or fasting plasma glucose vs control treatment groups was observed, regardless of diabetes status. CONCLUSION: This pooled analysis across 14 trials demonstrated similar safety for alirocumab vs control treatment, irrespective of diabetes status, except for more frequent local injection site reactions with alirocumab. People with diabetes reported fewer local injection site reactions than those without diabetes.

Use of vaccines and factors associated with their uptake variability in dogs, cats and rabbits attending a large sentinel network of veterinary practices across Great Britain.

Vaccination remains a mainstay of companion animal population health. However, how vaccine use at a population level complies with existing guidelines is unknown. Here we use electronic health records to describe vaccination in dogs, cats and rabbits attending a large sentinel network of UK veterinary practices. In total, 77.9% (95% CI: 77.6-78.1) of animals had recorded vaccinations. The percentage of animals with recorded vaccinations was higher in dogs, neutered animals, in insured dogs and cats and in purebred dogs. Vaccination rates varied in different regions of Great Britain in all species. Dogs and cats belonging to owners living in less deprived areas of England and Scotland were more likely to be recorded as vaccinated. In the vaccinated population, cats received more core vaccines per year of life (0.86) than dogs (0.75), with feline leukaemia vaccines almost as frequent as core vaccines. In dogs, leptospira vaccines were more frequent than core vaccines. This descriptive study suggests a substantial proportion of animals are not benefiting from vaccine protection. For the first time, we identify potential factors associated with variations in recorded vaccination frequency, providing a critical baseline against which to monitor future changes in companion animal vaccination and evidence to inform future targeted health interventions.

Optical trapping and optical force positioning of two-dimensional materials.

In recent years, considerable effort has been devoted to the synthesis and characterization of two-dimensional materials. Liquid phase exfoliation (LPE) represents a simple, large-scale method to exfoliate layered materials down to mono- and few-layer flakes. In this context, the contactless trapping, characterization, and manipulation of individual nanosheets hold perspectives for increased accuracy in flake metrology and the assembly of novel functional materials. Here, we use optical forces for high-resolution structural characterization and precise mechanical positioning of nanosheets of hexagonal boron nitride, molybdenum disulfide, and tungsten disulfide obtained by LPE. Weakly optically absorbing nanosheets of boron nitride are trapped in optical tweezers. The analysis of the thermal fluctuations allows a direct measurement of optical forces and the mean flake size in a liquid environment. Measured optical trapping constants are compared with T-matrix light scattering calculations to show a quadratic size scaling for small size, as expected for a bidimensional system. In contrast, strongly absorbing nanosheets of molybdenum disulfide and tungsten disulfide are not stably trapped due to the dominance of radiation pressure over the optical trapping force. Thus, optical forces are used to pattern a substrate by selectively depositing nanosheets in short times (minutes) and without any preparation of the surface. This study will be useful for improving ink-jet printing and for a better engineering of optoelectronic devices based on two-dimensional materials.

Patterns of antimicrobial agent prescription in a sentinel population of canine and feline veterinary practices in the United Kingdom.

Antimicrobial resistance is an increasingly important global health threat and the use of antimicrobial agents is a key risk factor in its development. This study describes antimicrobial agent prescription (AAP) patterns over a 2year period using electronic health records (EHRs) from booked consultations in a network of 457 sentinel veterinary premises in the United Kingdom. A semi-automated classification methodology was used to map practitioner defined product codes in 918,333 EHRs from 413,870 dogs and 352,730 EHRs from 200,541 cats, including 289,789 AAPs. AAP as a proportion of total booked consultations was more frequent in dogs (18.8%, 95% confidence interval, CI, 18.2-19.4) than cats (17.5%, 95% CI 16.9-18.1). Prescription of topical antimicrobial agents was more frequent in dogs (7.4%, 95% CI 7.2-7.7) than cats (3.2%, 95% CI 3.1-3.3), whilst prescription of systemic antimicrobial agents was more frequent in cats (14.8%, 95% CI 14.2-15.4) than dogs (12.2%, 95% CI 11.7-12.7). A decreasing temporal pattern was identified for prescription of systemic antimicrobial agents in dogs and cats. Premises which prescribed antimicrobial agents frequently for dogs also prescribed frequently for cats. AAP was most frequent during pruritus consultations in dogs and trauma consultations in cats. Clavulanic acid potentiated amoxicillin was the most frequently prescribed antimicrobial agent in dogs (28.6% of prescriptions, 95% CI 27.4-29.8), whereas cefovecin, a third generation cephalosporin, was the most frequently prescribed antimicrobial agent in cats (36.2%, 95% CI 33.9-38.5). This study demonstrated patterns in AAP over time and for different conditions in a population of companion animals in the United Kingdom.

Synthesis maps: visual knowledge translation for the CanIMPACT clinical system and patient cancer journeys.

Salient findings and interpretations from the canimpact clinical cancer research study are visually represented in two synthesis maps for the purpose of communicating an integrated presentation of the study to clinical cancer researchers and policymakers. Synthesis maps integrate evidence and expertise into a visual narrative for knowledge translation and communication. A clinical system synthesis map represents the current Canadian primary care and cancer practice systems, proposed as a visual knowledge translation from the mixed-methods canimpact study to inform Canadian clinical research, policy, and practice discourses. Two synthesis maps, drawn together from multiple canimpact investigations and sources, were required to articulate critical differences between the clinical system and patient perspectives. The synthesis map of Canada-wide clinical cancer systems illustrates the relationships between primary care and the full cancer continuum. A patient-centred map was developed to represent the cancer (and primary care) journeys as experienced by breast and colorectal cancer patients.

Optical manipulation using highly focused alternate radially and azimuthally polarized beams modulated by a devil's lens.

We propose and demonstrate a novel high numerical aperture (NA) focusing system composed of an annular beam with alternate radially and azimuthally polarized rings, focused by a devil's lens (DL), and further investigate its radiation forces acting upon a Rayleigh particle both analytically and numerically. Strongly focused cylindrical vector beams produce either dark-centered or peak-centered intensity distributions depending on the state of polarization, whereas the DL produces a series of foci along the propagation direction. We exploit these focusing properties and show that by selecting an appropriate truncation parameter in front of the focusing lens, the proposed optical focusing system can selectively trap and manipulate dielectric micro-particles with low or high refractive indices by simply adjusting the radius of the pupil or the beam. Finally, the stability conditions for effectively trapping and manipulating Rayleigh particles are analyzed. The results obtained in this work are of interest in possible applications in optical confinement and manipulation, sorting micro-particles, and making use of a DL.

Canine babesiosis and tick activity monitored using companion animal electronic health records in the UK.

Recent publications highlighting autochthonous Babesia canis infection in dogs from Essex that have not travelled outside the UK are a powerful reminder of the potential for pathogen emergence in new populations. Here the authors use electronic health data collected from two diagnostic laboratories and a network of 392 veterinary premises to describe canine Babesia cases and levels of Babesia concern from January 2015 to March 2016, and the activity of ticks during December 2015-March 2016. In most areas of the UK, Babesia diagnosis in this population was rare and sporadic. In addition, there was a clear focus of Babesia cases in the affected area in Essex. Until February 2016, analysis of health records indicated only sporadic interest in Babesia largely in animals coming from overseas. Following media coverage in March 2016, there was a spike in owner concern that was geographically dispersed beyond the at-risk area. Tick activity (identified as ticks being removed from animals in veterinary consultations) was consistent but low during the period preceding the infections (<5 ticks/10,000 consultations), but increased in March. This highlights the use of electronic health data to describe rapidly evolving risk and concern that follows the emergence of a pathogen.

Radiation forces on a Rayleigh particle by highly focused radially polarized beams modulated by DVL.

The intensity and the radiation forces acting on a Rayleigh particle near the focus of completely coherent radially polarized beams whose phase are modulated by a devil's vortex-lens (DVL) are studied. The influence of the structure of a DVL on the radiation force distribution is analyzed. It is found by numerical simulations that the modulated beams show a clear advantage over the unmodulated highly focused radially polarized beams, as the modulated beam can simultaneously trap and manipulate the multiple Rayleigh particles, while the unmodulated beam can trap only one particle under the same condition.

Devil's lens optical tweezers.

We demonstrate an optical tweezers using a laser beam on which is imprinted a focusing phase profile generated by a Devil's staircase fractal structure (Cantor set). We show that a beam shaped in this way is capable of stably trapping a variety of micron- and submicron-sized particles and calibrate the optical trap as a function of the control parameters of the fractal structure, and explain the observed variation as arising from radiation pressure exerted by unfocused parts of the beam in the region of the optical trap. Experimental results are complemented by calculation of the structure of the focus in the regime of high numerical aperture.

Exact, time-independent estimation of clone size distributions in normal and mutated cells.

Biological tools such as genetic lineage tracing, three-dimensional confocal microscopy and next-generation DNA sequencing are providing new ways to quantify the distribution of clones of normal and mutated cells. Understanding population-wide clone size distributions in vivo is complicated by multiple cell types within observed tissues, and overlapping birth and death processes. This has led to the increased need for mathematically informed models to understand their biological significance. Standard approaches usually require knowledge of clonal age. We show that modelling on clone size independent of time is an alternative method that offers certain analytical advantages; it can help parametrize these models, and obtain distributions for counts of mutated or proliferating cells, for example. When applied to a general birth-death process common in epithelial progenitors, this takes the form of a gambler's ruin problem, the solution of which relates to counting Motzkin lattice paths. Applying this approach to mutational processes, alternative, exact, formulations of classic Luria-Delbrück-type problems emerge. This approach can be extended beyond neutral models of mutant clonal evolution. Applications of these approaches are twofold. First, we resolve the probability of progenitor cells generating proliferating or differentiating progeny in clonal lineage tracing experiments in vivo or cell culture assays where clone age is not known. Second, we model mutation frequency distributions that deep sequencing of subclonal samples produce.

Surveillance of diarrhoea in small animal practice through the Small Animal Veterinary Surveillance Network (SAVSNET).

Using the Small Animal Veterinary Surveillance Network (SAVSNET), a national small animal disease-surveillance scheme, information on gastrointestinal disease was collected for a total of 76 days between 10 May 2010 and 8 August 2011 from 16,223 consultations (including data from 9115 individual dogs and 3462 individual cats) from 42 premises belonging to 19 UK veterinary practices. During that period, 7% of dogs and 3% of cats presented with diarrhoea. Adult dogs had a higher proportional morbidity of diarrhoea (PMD) than adult cats (P <0.001). This difference was not observed in animals <1 year old. Younger animals in both species had higher PMDs than adult animals (P < 0.001). Neutering was associated with reduced PMD in young male dogs. In adult dogs, miniature Schnauzers had the highest PMD. Most animals with diarrhoea (51%) presented having been ill for 2-4 days, but a history of vomiting or haemorrhagic diarrhoea was associated with a shorter time to presentation. The most common treatments employed were dietary modification (66% of dogs; 63% of cats) and antibacterials (63% of dogs; 49% of cats). There was variability in PMD between different practices. The SAVNET methodology facilitates rapid collection of cross-sectional data regarding diarrhoea, a recognised sentinel for infectious disease, and characterises data that could benchmark clinical practice and support the development of evidence-based medicine.

Inter-observer agreement, diagnostic sensitivity and specificity of animal-based indicators of young lamb welfare.

A scientific literature review and consensus of expert opinion used the welfare definitions provided by the Farm Animal Welfare Council (FAWC) Five Freedoms as the framework for selecting a set of animal-based indicators that were sensitive to the current on-farm welfare issues of young lambs (aged ≤ 6 weeks). Ten animal-based indicators assessed by observation - demeanour, response to stimulation, shivering, standing ability, posture, abdominal fill, body condition, lameness, eye condition and salivation were tested as part of the objective of developing valid, reliable and feasible animal-based measures of lamb welfare The indicators were independently tested on 966 young lambs from 17 sheep flocks across Northwest England and Wales during December 2008 to April 2009 by four trained observers. Inter-observer reliability was assessed using Fleiss's kappa (κ), and the pair-wise agreement with an experienced, observer designated as the 'test standard observer' (TSO) was examined using Cohen's κ. Latent class analysis (LCA) estimated the sensitivity (Se) and specificity (Sp) of each observer without assuming a gold standard and predicted the Se and Sp of randomly selected observers who may apply the indicators in the future. Overall, good levels of inter-observer reliability, and high levels of Sp were identified for demeanour (κ = 0.54, Se ≥ 0.70, Sp ≥ 0.98), stimulation (κ = 0.57, Se = 0.30 to 0.77, Sp ≥ 0.98), shivering (κ = 0.55, Se = 0.37 to 0.85, Sp ≥ 0.99), standing ability (0.54, Se ≥ 0.80, Sp ≥ 0.99), posture (κ = 0.45, Se ≥ 0.56, Sp = 0.99), abdominal fill (κ = 0.44, Se = 0.39 to 0.98, Sp = 0.99), body condition (κ = 0.72, Se ⩾ 0.38 to 0.90, Sp = 0.99), lameness (κ = 0.68, Se > 0.73, Sp = 1.00), and eye condition (κ = 0.72, Se ≥ 0.86, Sp = 0.99). LCA predicted that randomly selected observers had Se > 0.77 (acceptable), and Sp ≥ 0.98 (high) for assessments of demeanour, lameness, abdominal fill posture, body condition and eye condition. The diagnostic performance of some indicators was influenced by the composition of the study population, and it would be useful to test the indicators on lambs with a greater level of outcomes associated with poor welfare. The findings presented in this paper could be applied in the selection of valid, reliable and feasible indicators used for the purposes of on-farm assessments of lamb welfare.

Trapping volume control in optical tweezers using cylindrical vector beams.

We present the result of an investigation into the optical trapping of spherical microparticles using laser beams with a spatially inhomogeneous polarization direction [cylindrical vector beams (CVBs)]. We perform three-dimensional tracking of the Brownian fluctuations in the position of a trapped particle and extract the trap spring constants. We characterize the trap geometry by the aspect ratio of spring constants in the directions transverse and parallel to the beam propagation direction and evaluate this figure of merit as a function of polarization angle. We show that the additional degree of freedom present in CVBs allows us to control the optical trap strength and geometry by adjusting only the polarization of the trapping beam. Experimental results are compared with a theoretical model of optical trapping using CVBs derived from electromagnetic scattering theory in the T-matrix framework.

Unilateral transverse cordotomy for bilateral abductor vocal fold immobility.

OBJECTIVE: We present a case series with airway compromise due to bilateral abductor vocal fold paralysis or fixation, treated with unilateral transverse cordotomy. METHODS: Of eight consecutive patients with dyspnoea due to bilateral paramedian vocal fold immobility, seven underwent unilateral transverse cordotomy between August 2006 and April 2010 at University Hospital of South Manchester, UK. Airway and voice outcomes were compared before and after surgery. RESULTS: All seven treated cases derived subjective airway function improvement; there was no aspiration. The eighth case had inadequate access. None of the seven treated patients required contralateral cordotomy or permanent tracheostomy. One treated case required a temporary tracheostomy; unilateral transverse cordotomy facilitated eventual decannulation. Two patients died of cancer at five and six weeks, variously. At a mean follow up of 22 months, four cases showed unchanged or slightly worse Voice Symptom Scale and Grade-Roughness-Breathiness-Asthenia-Strain scale scores. CONCLUSION: In patients with bilateral abductor vocal fold immobility, unilateral transverse cordotomy results in improved dyspnoea with either no voice change or only slight worsening. This is a more conservative procedure than bilateral transverse cordotomy, with the potential for better preservation of voice and breath support.

Optical trapping of nanotubes with cylindrical vector beams.

We use laser beams with radial and azimuthal polarization to optically trap carbon nanotubes. We measure force constants and trap parameters as a function of power showing improved axial trapping efficiency with respect to linearly polarized beams. The analysis of the thermal fluctuations highlights a significant change in the optical trapping potential when using cylindrical vector beams. This enables the use of polarization states to shape optical traps according to the particle geometry, as well as paving the way to nanoprobe-based photonic force microscopy with increased performance compared to a standard linearly polarized configuration.

Antibacterial prescribing patterns in small animal veterinary practice identified via SAVSNET: the small animal veterinary surveillance network.

In this study, data from veterinary clinical records were collected via the small animal veterinary surveillance network (SAVSNET). Over a three-month period, data were obtained from 22,859 consultations at 16 small animal practices in England and Wales: 69 per cent from dogs, 24 per cent from cats, 3 per cent from rabbits and 4 per cent from miscellaneous species. The proportion of consults where prescribing of antibacterials was identified was 35.1 per cent for dogs, 48.5 per cent for cats and 36.6 per cent for rabbits. Within this population, 76 per cent of antibacterials prescribed were ß-lactams, including the most common group of clavulanic acid-potentiated amoxicillin making up 36 per cent of the antibacterials prescribed. Other classes included lincosamides (9 per cent), fluoroquinolones and quinolones (6 per cent) and nitroimidazoles (4 per cent). Vancomycin and teicoplanin (glycopeptide class), and imipenem and meropenem (ß-lactam class) prescribing was not identified. Prescribing behaviour varied between practices. For dogs and cats, the proportion of consults associated with the prescription of antibacterials ranged from 0.26 to 0.55 and 0.41 to 0.73, respectively.