Practice patterns in management of differentiated thyroid cancer since the 2014 British Thyroid Association (BTA) guidelines.

BACKGROUND: The updated 2014 BTA guidelines emphasised a more conservative, risk adapted model for the management of low-risk differentiated thyroid cancer (DTC). In comparison to historical approach of total thyroidectomy combined with radioactive iodine, treatment de-escalation is increasingly supported. AIMS: To evaluate the impact of the updated BTA guidelines on the management of DTC cases at regional UK centre. METHODS: All DTC patients were retrospectively identified from regional thyroid MDT database between Jan2009-Dec2020. Oncological treatment and clinico-pathological characteristics were analysed. RESULTS: 623 DTC cases were identified; 312 (247 female: 65 male) between 2009 and 2014 and 311 (225 female: 86 male) between 2015 and 2020. Median age is 48 years (range 16-85). By comparing pre- and post-2015 cohorts, there was a significant drop in total thyroidectomy (87.1% vs 76.8%, p = 0.001) and the use of radioactive iodine (RAI) (73.1% vs 62.1%, p = 0.003) in our post-2015 cohort. When histological adverse features were analysed, extra-thyroidal extension (4.2% vs 17.0%, p=< 0.001), lymphovascular invasion (31.4% vs 50.5%, p=<0.001) and multi-centricity (26.9% vs 43.4%, p = 0.001) were significantly increased in the post 2015 cohort. Nonetheless, total thyroidectomy (TT) remains the treatment choice for low risk T1/2 N0 M0 disease in 65.3% (124/190) in post-2015 cohort for several reasons. Reasons include adverse histological features (50.8%), benign indications (32.5%), contralateral nodules (11.7%), patient preference (2.5%), and diagnostic uncertainty (2.5%). CONCLUSION: Our study confirms a move towards a more conservative approach to patients with low-risk DTC in the UK, which is in keeping with the BTA 2014 guideline and international trends, but total thyroidectomy remains prevalent for low risk T1/2 N0 M0 disease for other reasons.

Oncological outcomes in differentiated thyroid cancer in South East Scotland.

BACKGROUND: Differentiated thyroid cancer (DTC) is increasing in incidence but little is known about oncological outcomes for patients treated in the UK. Internationally there is a move toward conservative treatment of DTC. However, this is based on evidence from outside the UK. The aim of this study was to analyse oncological outcomes for a contemporary cohort of patients treated in a UK centre. METHODS: Review of 470 consecutive prospectively recorded cases of DTC from the South East of Scotland endocrine MDT 2009-2018. Data on patient, tumour and treatment details as well as recurrence and survival details were extracted from the electronic patient record. RESULTS: Of 470 patients female:male ratio was 3.4:1, median age at presentation was 48 years (range 16-86 years). Overall 193 (41%), 134 (29%), 119 (25%) and 22 (5%) patients were p T1, T2, T3, and p T4 respectively. 385 patients (82%) were pN0, 31 patients (7%) were pN1a and 53 patients (11%) were pN1b. 19 patients (4%) were M1. Of 470 patients 350 (74%) had papillary thyroid carcinoma, 120 patients (26%) had follicular carcinoma. Surgical management was lobectomy, isthumusectomy, total thyroidectomy and lobectomy then completion thyroidectomy in 14%,1%, 41% and 43% cases respectively. 64% patients received radioactive Iodine (RAI) therapy. With a median follow-up of 70 months (range 4-124 months), 5 years overall survival and disease specific survival were 96.7% and 98.5% respectively. The 5 year local recurrence free survival (LRFS), regional recurrence free survival (RRFS), locoregional recurrence free survival (LRRFS), distant recurrence free survival (DRFS) and any recurrence free survivals were 100%, 95.8%, 95.8%, 98.3% and 95% respectively. CONCLUSION: Oncological outcomes for patients treated with DTC were excellent, in keeping with experience from international groups, suggesting that a move towards conservative treatment in the UK seems reasonable.

Clinicopathological features of Differentiated Thyroid Cancer presenting in the UK versus internationally: An observational cohort study.

INTRODUCTION: Very little data are available regarding differentiated thyroid cancer (DTC) managed in the UK, and no UK patients are included in the evidence base upon which international guidelines are based. Therefore, the aim of this study was to compare the clinicopathological features of patients with DTC presenting in a UK population with international patient cohorts. PATIENTS AND METHODS: Data were collected from a prospectively held multi-disciplinary team records from January 2009 to December 2016. The local cohort was compared with cohorts from across the world based on clinicopathological features. Ethical approval was obtained by Lothian Caldicott Guardian (Ref 16 133). RESULTS: 444 cases were diagnosed locally with a median age of 48 years (range 16-86 years). 78% of patients were female. 25% of our patients had follicular carcinoma with an overall N1 rate of 20%. Distant disease was recorded in 5% cases. In comparison with international data, our local cohort had a higher rate of follicular thyroid carcinoma. Variation was seen in terms of age, gender distribution, primary tumour size, nodal and distant disease. In Korea, where thyroid cancer screening has been undertaken, smaller tumours, higher rates of nodal disease and lower rates of distant disease are described. CONCLUSION: In our centre, a higher rate of males is treated with larger primary disease and a higher percentage of follicular carcinoma. The reasons for this geographic variation in clinicopathological features in the UK are unclear. As a result, caution should be applied in translating the international move towards a more conservative approach to DTC in the UK in comparison with other areas of the world.

Squeezing and over-squeezing of triphotons.

Quantum mechanics places a fundamental limit on the accuracy of measurements. In most circumstances, the measurement uncertainty is distributed equally between pairs of complementary properties; this leads to the 'standard quantum limit' for measurement resolution. Using a technique known as 'squeezing', it is possible to reduce the uncertainty of one desired property below the standard quantum limit at the expense of increasing that of the complementary one. Squeezing is already being used to enhance the sensitivity of gravity-wave detectors and may play a critical role in other high precision applications, such as atomic clocks and optical communications. Spin squeezing (the squeezing of angular momentum variables) is a powerful tool, particularly in the context of quantum light-matter interfaces. Although impressive gains in squeezing have been made, optical spin-squeezed systems are still many orders of magnitude away from the maximum possible squeezing, known as the Heisenberg uncertainty limit. Here we demonstrate how an optical system can be squeezed essentially all the way to this fundamental bound. We construct spin-squeezed states by overlapping three indistinguishable photons in an optical fibre and manipulating their polarization (spin), resulting in the formation of a squeezed composite particle known as a 'triphoton'. The symmetry properties of polarization imply that the measured triphoton states can be most naturally represented by quasi-probability distributions on the surface of a sphere. In this work we show that the spherical topology of polarization imposes a limit on how much squeezing can occur, leading to the quasi-probability distributions wrapping around the sphere-a phenomenon we term 'over-squeezing'. Our observations of spin-squeezing in the few-photon regime could lead to new quantum resources for enhanced measurement, lithography and information processing that can be precisely engineered photon-by-photon.

Albumin modulates S1P delivery from red blood cells in perfused microvessels: mechanism of the protein effect.

Removal of plasma proteins from perfusates increases vascular permeability. The common interpretation of the action of albumin is that it forms part of the permeability barrier by electrostatic binding to the endothelial glycocalyx. We tested the alternate hypothesis that removal of perfusate albumin in rat venular microvessels decreased the availability of sphingosine-1-phosphate (S1P), which is normally carried in plasma bound to albumin and lipoproteins and is required to maintain stable baseline endothelial barriers (Am J Physiol Heart Circ Physiol 303: H825-H834, 2012). Red blood cells (RBCs) are a primary source of S1P in the normal circulation. We compared apparent albumin permeability coefficients [solute permeability (Ps)] measured using perfusates containing albumin (10 mg/ml, control) and conditioned by 20-min exposure to rat RBCs with Ps when test perfusates were in RBC-conditioned protein-free Ringer solution. The control perfusate S1P concentration (439 ± 46 nM) was near the normal plasma value at 37 °C and established a stable baseline Ps (0.9 ± 0.4 × 10(-6) cm/s). Ringer solution perfusate contained 52 ± 8 nM S1P and increased Ps more than 10-fold (16.1 ± 3.9 × 10(-6) cm/s). Consistent with albumin-dependent transport of S1P from RBCs, S1P concentrations in RBC-conditioned solutions decreased as albumin concentration, hematocrit, and temperature decreased. Protein-free Ringer solution perfusates that used liposomes instead of RBCs as flow markers failed to maintain normal permeability, reproducing the "albumin effect" in these mammalian microvessels. We conclude that the albumin effect depends on the action of albumin to facilitate the release and transport of S1P from RBCs that normally provide a significant amount of S1P to the endothelium.

Microvascular permeability to water is independent of shear stress, but dependent on flow direction.

Endothelial cells in a cultured monolayer change from a "cobblestone" configuration when grown under static conditions to a more elongated shape, aligned with the direction of flow, after exposure to sustained uniform shear stress. Sustained blood flow acts to protect regions of large arteries from injury. We tested the hypothesis that the stable permeability state of individually perfused microvessels is also characteristic of flow conditioning. In individually perfused rat mesenteric venular microvessels, microvascular permeability, measured as hydraulic conductivity (Lp), was stable [mean 1.0 × 10(-7) cm/(s × cmH2O)] and independent of shear stress (3-14 dyn/cm(2)) for up to 3 h. Vessels perfused opposite to the direction of normal blood flow exhibited a delayed Lp increase [ΔLp was 7.6 × 10(-7) cm/(s × cmH2O)], but the increase was independent of wall shear stress. Addition of chondroitin sulfate and hyaluronic acid to perfusates increased the shear stress range, but did not modify the asymmetry in response to flow direction. Increased Lp in reverse-perfused vessels was associated with numerous discontinuities of VE-cadherin and occludin, while both proteins were continuous around the periphery of forward-perfused vessels. The results are not consistent with a general mechanism for graded shear-dependent permeability increase, but they are consistent with the idea that a stable Lp under normal flow contributes to prevention of edema formation and also enables physiological regulation of shear-dependent small solute permeabilities (e.g., glucose). The responses during reverse flow are consistent with reports that disturbed flows result in a less stable endothelial barrier in venular microvessels.

A quantitative assessment of the number of disease foci in papillary thyroid cancer.

AIM: Multifocality is a frequent feature of papillary thyroid carcinoma (PTC). Its prognostic value is controversial although national guidelines recommend treatment intensification if present. However, multifocality is not a binary but discrete variable. This study aimed to examine the association between increasing number of foci and risk of recurrence following treatment. METHODS: 577 patients with PTC were identified with median follow-up of 61 months. Number of foci were taken from pathology reports. Log-rank test was used to assess significance. Multivariate analysis was performed and Hazard Ratios were calculated. RESULTS: Of 577 patients, 206(35%) had multifocal disease and 36(6%) recurred. 133(23%), 89(15%) and 61(11%) had 3+, 4+ or 5+ foci respectively. The 5-year RFS stratified by number of foci was 95%v93% for 2+foci (p = 0.616), 95%v96% for 3+foci (p = 0.198) and 89%v96% for 4+foci (p = 0.022). The presence of 4 foci was associated with an over 2-fold risk of recurrence (HR 2.296, 95% CI 1.106-4.765, p = 0.026) although this was not independent of TNM staging. Of the 206 multifocal patients, 31(5%) had 4+foci as their sole risk factor for treatment intensification. CONCLUSION: Although multifocality per se does not confer worse outcome in PTC, finding 4+foci is associated with worse outcome and could therefore be appropriate as a cut-off for treatment intensification. In our cohort, 5% of patients had 4+foci as a sole indication for treatment intensification, suggesting that such a cut off could impact clinical management.

Erythrocyte-derived sphingosine-1-phosphate stabilizes basal hydraulic conductivity and solute permeability in rat microvessels.

Exogenous sphingosine-1-phosphate (S1P), a lipid mediator in blood, attenuates acute microvascular permeability increases via receptor S1P1 to stabilize the endothelium. To evaluate the contribution of erythrocytes as an endogenous source of S1P to the regulation of basal permeability, we measured permeability coefficients in intact individually perfused venular microvessels of rat mesentery. This strategy also enabled the contributions of other endogenous S1P sources to be evaluated. Apparent permeability coefficients (P(S)) to albumin and α-lactalbumin and the hydraulic conductivity of mesenteric microvessels were measured in the presence or absence of rat erythrocytes or rat erythrocyte-conditioned perfusate. Rat erythrocytes added to the perfusate were the principal source of S1P in these microvessels. Basal P(S) to albumin was stable and typical of blood-perfused microvessels (mean 0.5 × 10(-6) cm/s) when erythrocytes or erythrocyte-conditioned perfusates were present. When they were absent, P(S) to albumin or α-lactalbumin increased up to 40-fold (over 10 min). When exogenous S1P was added to perfusates, permeability returned to levels comparable with those seen in the presence of erythrocytes. Addition of SEW 2871, an agonist specific for S1P1, in the absence of red blood cells reduced P(S)(BSA) (40-fold reduction) toward basal. The specific S1P1 receptor antagonist (W-146) reversed the stabilizing action of erythrocytes and increased permeability (27-fold increase) in a manner similar to that seen in the absence of erythrocytes. Erythrocytes are a primary source of S1P that maintains normal venular microvessel permeability. Absence of erythrocytes or conditioned perfusate in in vivo and in vitro models of endothelial barriers elevates basal permeability.

Attenuation by sphingosine-1-phosphate of rat microvessel acute permeability response to bradykinin is rapidly reversible.

To evaluate the hypothesis that sphingosine-1-phosphate (S1P) and cAMP attenuate increased permeability of individually perfused mesenteric microvessels through a common Rac1-dependent pathway, we measured the attenuation of the peak hydraulic conductivity (L(p)) in response to the inflammatory agent bradykinin (BK) by either S1P or cAMP. We varied the extent of exposure to each agent (test) and measured the ratio L(p)(test)/L(p)(BK alone) for each vessel (anesthetized rats). S1P (1 µM) added at the same time as BK (concurrent, no pretreatment) was as effective to attenuate the response to BK (L(p) ratio: 0.14 ± 0.05; n = 5) as concurrent plus pretreatment with S1P for 30 min (L(p) ratio: 0.26 ± 0.06; n = 11). The same pretreatment with S1P, but with no concurrent S1P, caused no inhibition of the BK response (L(p) ratio 1.07 ± 0.11; n = 8). The rapid on and off action of S1P demonstrated by these results was in contrast to cAMP-dependent changes induced by rolipram and forskolin (RF), which developed more slowly, lasted longer, and resulted in partial inhibition when given either as pretreatment or concurrent with BK. In cultured endothelium, there was no Rac activation or peripheral cortactin localization at 1 min with RF, but cortactin localization and Rac activation were maximal at 1 min with S1P. When S1P was removed, Rac activation returned to control within 2 min. Because of such differing time courses, S1P and cAMP are unlikely to act through fully common effector mechanisms.

Convolutional dictionary learning for blind deconvolution of optical coherence tomography images.

In this study, we demonstrate a sparsity-regularized, complex, blind deconvolution method for removing sidelobe artefacts and stochastic noise from optical coherence tomography (OCT) images. Our method estimates the complex scattering amplitude of tissue on a line-by-line basis by estimating and deconvolving the complex, one-dimensional axial point spread function (PSF) from measured OCT A-line data. We also present a strategy for employing a sparsity weighting mask to mitigate the loss of speckle brightness within tissue-containing regions caused by the sparse deconvolution. Qualitative and quantitative analyses show that this approach suppresses sidelobe artefacts and background noise better than traditional spectral reshaping techniques, with negligible loss of tissue structure. The technique is particularly useful for emerging OCT applications where OCT images contain strong specular reflections at air-tissue boundaries that create large sidelobe artefacts.

Transient regulation of transport by pericytes in venular microvessels via trapped microdomains.

A phenomenon that has defied explanation for two decades is the time scale for transient reabsorption in the classic experiments of Michel and Phillips on individually perfused frog mesentery microvessels. One finds that transient reabsorption lasts <2 min before a new steady state of low filtration is established when the lumen pressure is abruptly dropped from a high to a low value. Our experiments in frog and rat venular microvessels under a variety of conditions revealed the same time trend for new steady states to be established as in Michel and Phillips' experiments. In contrast, one theoretically predicts herein that the time required for the tissue albumin concentration to increase to values for a new steady state to be achieved through reabsorption is in the order of several hours. In this paper we propose a new hypothesis and theoretical model for this rapid regulation, namely that pericytes covering the interendothelial cleft exits create small trapped microdomains outside the cleft exits which regulate this transient behavior. Our electron microscopy studies on rat mesenteric venular microvessels reveal an average pericyte coverage of approximately 85%. The theoretical model based on this ultrastructural study predicts an equilibration time on the order of 1 min when the lumen pressure is abruptly lowered. The basic concept of a trapped microdomain can also be extended to microdomains in the interstitial space surrounding skeletal muscle capillaries.

Transnasal humidified rapid-insufflation ventilatory exchange ('THRIVE') in the coronavirus disease 2019 pandemic.

BACKGROUND: Since the start of the coronavirus disease 2019 pandemic, transnasal humidified rapid-insufflation ventilatory exchange ('THRIVE') has been classified as a high-risk aerosol-generating procedure and is strongly discouraged, despite a lack of conclusive evidence on its safety. METHODS: This study aimed to investigate the safety of transnasal humidified rapid-insufflation ventilatory exchange usage and its impact on staff members. A prospective study was conducted on all transnasal humidified rapid-insufflation ventilatory exchange cases performed in our unit between March and July 2020. RESULTS: During the study period, 18 patients with a variety of airway pathologies were successfully managed with transnasal humidified rapid-insufflation ventilatory exchange. For each case, 7-10 staff members were present. Appropriate personal protective equipment protocols were strictly implemented and adhered to. None of the staff involved reported symptoms or tested positive for coronavirus disease 2019, up to at least a month following their exposure to transnasal humidified rapid-insufflation ventilatory exchange. CONCLUSION: With strictly correct personal protective equipment use, transnasal humidified rapid-insufflation ventilatory exchange can be safely employed for carefully selected patients in the current pandemic, without jeopardising the health and safety of the ENT and anaesthetic workforce.

Improving quantum state estimation with mutually unbiased bases.

When used in quantum state estimation, projections onto mutually unbiased bases have the ability to maximize information extraction per measurement and to minimize redundancy. We present the first experimental demonstration of quantum state tomography of two-qubit polarization states to take advantage of mutually unbiased bases. We demonstrate improved state estimation as compared to standard measurement strategies and discuss how this can be understood from the structure of the measurements we use. We experimentally compared our method to the standard state estimation method for three different states and observe that the infidelity was up to 1.84 ± 0.06 times lower by using our technique than it was by using standard state estimation methods.

A piezoelectric bone-conduction bending hearing actuator.

A prototype of a novel bone-conduction hearing actuator based on a piezoelectric bending actuator is presented. The device lies flat against the skull which would allow it to form the basis of a subcutaneous bone-anchored hearing aid. The actuator excites bending in bone through a local bending moment rather than the application of a point force as with conventional bone-anchored hearing aids. Through measurements of the cochlear velocity created by the actuator in embalmed human heads, the device is shown to exhibit high efficiency, making it a possible alternative to present-day electromagnetic bone-vibration actuators.

Role of macrophages in normal wound healing: an overview.

Macrophages play an essential role during inflammation in normal wound healing. They promote the recruitment and proliferation of fibroblasts, and express some of the key growth factors that stimulate angiogenesis.

The impact of completion thyroidectomy.

INTRODUCTION: The oncological benefit of completion thyroidectomy (CT) following thyroid lobectomy (TL) is presumed to be similar to that of upfront total thyroidectomy(TT), from a patient's perspective the risk and inconvenience of further surgery adds significantly to the impact of the overall treatment. The aim of this study is to assess the impact of CT in terms of the duration of admission and associated complications. METHODS: A study of consecutive patients with DTC identified from prospective MDT records of South-East Scotland from 2009 to 2015. Surgical data was extracted from electronic medical record. RESULTS: Of 361 patients diagnosed with DTC, 161 (45%) had CT. The median postoperative stay was 1 day (range 1-5days). In total 22 patients (14%)suffered complications. Four patients (3%) developed postoperative haematoma. Two (1%) had an identified permanent nerve palsy on the completion side. 13 patients (8%) remained on calcium supplementation for more than 6 months postoperatively and three patients (2%) developed wound complications. CONCLUSIONS: Our study confirms that CT is regularly performed (45%). Recent changes in international guidelines recognize increasing number of patients as eligible for a conservative approach but recommend CT based on whether upfront TT would have been recommended if the TL pathology were known from the outset. Such an approach fails to consider the additional risk and inconvenience of CT on the overall patient experience. Due to a relatively high rate of complications, only those patients who are most likely to benefit from further surgery to facilitate adjuvant radioactive iodine should be offered additional surgery.

Retrospective analysis of early steroid-induced adverse reactions in kidney and kidney-pancreas transplant recipients.

Corticosteroids (steroids) are associated with numerous adverse drug reactions (ADRs). Long-term ADRs are well characterized, but there are limited data on the incidence and likelihood of short-term ADRs. We sought to determine the incidence of ADRs potentially related to early administration of steroids in kidney and kidney-pancreas transplant recipients and to determine the probability that the ADR was due to the steroid. We retrospectively evaluated the records of all eligible kidney or pancreas-kidney transplants during 2003. ADRs were rated by two reviewers according to the Naranjo algorithm, and identified as "definite," "probable," "possible," or "doubtful." ADRs were identified in 100% of patients (n = 103) by 8.2 +/- 4.9 days. The mean ADRs per patient were 3.26 +/- 1.04. Weight gain occurred in 79.6%, hypertension in 71.8%, diabetes mellitus in 52.4%, hyperglycemia in 47.6%, leukocytosis in 31.1%, insomnia in 27.2%, anxiety in 10.7%, and psychosis in 1.9%. Based on mean interinvestigator score, leukocytosis was judged as "probable" and weight gain and psychosis were "possible to probable." Diabetes, hyperglycemia, hypertension, and insomnia were "possible" and anxiety was "possible to doubtful." These results provide evidence of the incidence and likelihood of early steroid-related ADRs.

Induction of monooxygenases in rhesus monkeys by 3-methylcholanthrene: metabolism and mutagenic activation of N-2-acetylaminofluorene and benzo(a)pyrene.

Induction of content and activity of hepatic and lung cytochrome P450-dependent monooxygenases by 3-methylcholanthrene (MCA) was studied in male rhesus monkeys. Hepatic microsomes were concomitantly studied for mutagenic activation of N-2-acetylaminofluorene (AAF) as well as with the use of sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Hepatic N-hydroxylation of AAF was increased sixfold to sevenfold after MCA treatment; aryl hydrocarbon hydroxylase was similarly increased in both liver and lung. The hepatic cytochrome P450 content was increased by 50%, and the Soret maximum in the CO-hemoprotein complex was shifted to the blue by 2 nm after MCA induction. Electrophoresis of hepatic microsomes from MCA-treated monkeys showed an increase in a polypeptide band of 54,000 molecular weight. Mutagenic activation of AAF by liver microsomes from untreated rhesus monkeys was low but was increased 40-fold after MCA treatment. No effect was observed on the mutagenic activation of N-hydroxy-2-acetylaminofluorene by liver microsomes after MCA treatment. Rhesus monkeys may provide a model for evaluation of the role of polycyclic hydrocarbon induction in chemically caused cancer and toxicity in primates.