Softening of the optical phonon by reduced interatomic bonding strength without depolarization.

Softening of the transverse optical (TO) phonon, which could trigger ferroelectric phase transition, can usually be achieved by enhancing the long-range Coulomb interaction over the short-range bonding force1, for example, by increasing the Born effective charges2. However, it suffers from depolarization effects3,4 as the induced ferroelectricity is suppressed on size reduction of the host materials towards high-density nanoscale electronics. Here, we present an alternative route to drive the TO phonon softening by showing that the abnormal soft TO phonon in rocksalt-structured ultrawide-bandgap BeO (ref. 5) is mainly induced by a substantial reduction in the short-range bonding interaction due to the Be-O bond stretching caused by an electron cloud-overlap-induced Coulomb repulsion between two adjacent oxygen ions that are arranged octahedrally around an extremely small Be ion. We further demonstrate the emergence of robust ferroelectricity in strain-induced perovskite BaZrO3 and ultrathin HfO2 and ZrO2 films6,7 grown epitaxially on lattice-mismatched SiO2/Si substrate arising from the softening of the TO phonon driven by a reduction in the short-range bonding strength of biaxial strain-induced stretching bonds. These findings shed light on developing a unified theory for ferroelectricity enhancement in ultrathin films free from depolarization fields by tailoring chemical bonds using ionic radius differences, strains, doping and lattice distortions.

Artificial Graphene Spin Polarized Electrode for Magnetic Tunnel Junctions.

2D materials offer the ability to expose their electronic structure to manipulations by a proximity effect. This could be harnessed to craft properties of 2D interfaces and van der Waals heterostructures in devices and quantum materials. We explore the possibility to create an artificial spin polarized electrode from graphene through proximity interaction with a ferromagnetic insulator to be used in a magnetic tunnel junction (MTJ). Ferromagnetic insulator/graphene artificial electrodes were fabricated and integrated in MTJs based on spin analyzers. Evidence of the emergence of spin polarization in proximitized graphene layers was observed through the occurrence of tunnel magnetoresistance. We deduced a spin dependent splitting of graphene's Dirac band structure (∼15 meV) induced by the proximity effect, potentially leading to full spin polarization and opening the way to gating. The extracted spin signals illustrate the potential of 2D quantum materials based on proximity effects to craft spintronics functionalities, from vertical MTJs memory cells to logic circuits.

Clinico-pathologic relationships with Ki67 and its change with short-term aromatase inhibitor treatment in primary ER + breast cancer: further results from the POETIC trial (CRUK/07/015).

PURPOSE: Ki67 assessed at diagnosis (Ki67baseline) is an important prognostic factor in primary oestrogen receptor-positive (ER +) breast cancer. Proportional change in Ki67 after 2 weeks (∆Ki672week) is associated with clinical benefit from endocrine therapies and residual Ki67 (Ki672week) with recurrence-free survival. The aim was to define the association between Ki67baseline and after aromatase inhibitor (AI) exposure ∆Ki672week and Ki672week with key prognostic and biologic factors utilising data from the POETIC study. PATIENTS AND METHODS: In POETIC 4480 postmenopausal patients with primary ER and/or PgR + breast cancer were randomised 2:1 to 2 weeks' presurgical AI (anastrozole or letrozole) or no presurgical treatment (control). Ki67 was measured centrally in core-cut biopsies taken prior to AI and in core-cuts or the excision biopsy at surgery. Relationships between the Ki67 and biologic factors were explored using linear regression. RESULTS: Established associations of Ki67baseline with biologic factors including PgR status, tumour grade, tumour size, histological subtype, nodal status, and vascular invasion were confirmed in the HER2- subpopulation. In the HER2 + subpopulation only grade and tumour size were significantly associated with Ki67baseline. In control group Ki672week was 18% lower than Ki67baseline (p < 0.001) when Ki672week was measured in excision biopsies but not when measured in core-cuts. Median suppression by AIs (∆Ki672week) was 79.3% (IQR: -89.9 to -54.6) and 53.7% (IQR: -78.9 to -21.1) for HER2-negative and HER2-positive cases, respectively. Significantly less suppression occurred in PgR- vs PgR + and HER2 + vs HER2- tumours which remained apparent after adjustment for 2-week sample type. CONCLUSIONS: The magnitude of this study allowed characterisation of relationships between Ki67baseline, ∆Ki672week and Ki672week with high degrees of confidence providing a reference source for other studies. Lower values of Ki67 occur when measured on excision biopsies and could lead to apparent but artefactual decreases in Ki67: this should be considered when either ∆Ki672week or Ki672week is used in routine clinical practice to aid treatment decisions or in clinical trials assessing new drug therapies.

Mitochondria Transplantation Mitigates Damage in an In Vitro Model of Renal Tubular Injury and in an Ex Vivo Model of DCD Renal Transplantation.

OBJECTIVES: To test whether mitochondrial transplantation (MITO) mitigates damage in 2 models of acute kidney injury (AKI). BACKGROUND: MITO is a process where exogenous isolated mitochondria are taken up by cells. As virtually any morbid clinical condition is characterized by mitochondrial distress, MITO may find a role as a treatment modality in numerous clinical scenarios including AKI. METHODS: For the in vitro experiments, human proximal tubular cells were damaged and then treated with mitochondria or placebo. For the ex vivo experiments, we developed a non-survival ex vivo porcine model mimicking the donation after cardiac death renal transplantation scenario. One kidney was treated with mitochondria, although the mate organ received placebo, before being perfused at room temperature for 24 hours. Perfusate samples were collected at different time points and analyzed with Raman spectroscopy. Biopsies taken at baseline and 24 hours were analyzed with standard pathology, immunohistochemistry, and RNA sequencing analysis. RESULTS: In vitro, cells treated with MITO showed higher proliferative capacity and adenosine 5'-triphosphate production, preservation of physiological polarization of the organelles and lower toxicity and reactive oxygen species production. Ex vivo, kidneys treated with MITO shed fewer molecular species, indicating stability. In these kidneys, pathology showed less damage whereas RNAseq analysis showed modulation of genes and pathways most consistent with mitochondrial biogenesis and energy metabolism and downregulation of genes involved in neutrophil recruitment, including IL1A, CXCL8, and PIK3R1. CONCLUSIONS: MITO mitigates AKI both in vitro and ex vivo.

Relationship between ER expression by IHC or mRNA with Ki67 response to aromatase inhibition: a POETIC study.

BACKGROUND: In clinical practice, oestrogen receptor (ER) analysis is almost entirely by immunohistochemistry (IHC). ASCO/CAP recommends cut-offs of < 1% (negative) and 1-10% (low) cells positive. There is uncertainty whether patients with ER low tumours benefit from endocrine therapy. We aimed to assess IHC and mRNA cut-points for ER versus biological response of primary breast cancer to 2 weeks' aromatase inhibitor treatment as measured by change in Ki67. METHODS: Cases were selected from the aromatase inhibitor treatment group of POETIC. We selected the 15% with the poorest Ki67 response (PR, < 40% Ki67 suppression, n = 230) and a random 30% of the remainder categorised as intermediate (IR, 40-79% Ki67 suppression, n = 150) and good-responders (GR, ≥ 80% Ki67 suppression, n = 230) from HER2 - group. All HER2 + cases available were selected irrespective of their response category (n = 317). ER expression was measured by IHC and qPCR. RESULTS: ER IHC was available from 515 HER2 - and 186 HER2 + tumours and ER qPCR from 367 HER2 - and 171 HER2 + tumours. Ninety-one percentage of patients with ER IHC < 10% were PRs with similar rates in HER2 - and HER2 + cases. At or above ER IHC 10% substantial numbers of patients showed IR or GR. Similar proportions of patients were defined by cut-points of ER IHC < 10% and ER mRNA < 5 units. In addition, loss of PgR expression altered ER anti-proliferation response with 92% of PgR - cases with ER IHC < 40% being PRs. CONCLUSIONS: There was little responsiveness at IHC < 10% and no distinction between < 1% and 1-10% cells positive. Similar separation of PRs from IR/GRs was achieved by IHC and mRNA.

Computationally modeling mammalian succinate dehydrogenase kinetics identifies the origins and primary determinants of ROS production.

Succinate dehydrogenase (SDH) is an inner mitochondrial membrane protein complex that links the Krebs cycle to the electron transport system. It can produce significant amounts of superoxide ([Formula: see text]) and hydrogen peroxide (H2O2); however, the precise mechanisms are unknown. This fact hinders the development of next-generation antioxidant therapies targeting mitochondria. To help address this problem, we developed a computational model to analyze and identify the kinetic mechanism of [Formula: see text] and H2O2 production by SDH. Our model includes the major redox centers in the complex, namely FAD, three iron-sulfur clusters, and a transiently bound semiquinone. Oxidation state transitions involve a one- or two-electron redox reaction, each being thermodynamically constrained. Model parameters were simultaneously fit to many data sets using a variety of succinate oxidation and free radical production data. In the absence of respiratory chain inhibitors, model analysis revealed the 3Fe-4S iron-sulfur cluster as the primary [Formula: see text] source. However, when the quinone reductase site is inhibited or the quinone pool is highly reduced, [Formula: see text] is generated primarily by the FAD. In addition, H2O2 production is only significant when the enzyme is fully reduced, and fumarate is absent. Our simulations also reveal that the redox state of the quinone pool is the primary determinant of free radical production by SDH. In this study, we showed the importance of analyzing enzyme kinetics and associated side reactions in a consistent, quantitative, and biophysically detailed manner using a diverse set of experimental data to interpret and explain experimental observations from a unified perspective.

Earlier diagnosis of lung cancer in a randomised trial of an autoantibody blood test followed by imaging.

The EarlyCDT-Lung test is a high-specificity blood-based autoantibody biomarker that could contribute to predicting lung cancer risk. We report on the results of a phase IV biomarker evaluation of whether using the EarlyCDT-Lung test and any subsequent computed tomography (CT) scanning to identify those at high risk of lung cancer reduces the incidence of patients with stage III/IV/unspecified lung cancer at diagnosis compared with the standard clinical practice at the time the study began.The Early Diagnosis of Lung Cancer Scotland (ECLS) trial was a randomised controlled trial of 12 208 participants at risk of developing lung cancer in Scotland in the UK. The intervention arm received the EarlyCDT-Lung test and, if test-positive, low-dose CT scanning 6-monthly for up to 2 years. EarlyCDT-Lung test-negative and control arm participants received standard clinical care. Outcomes were assessed at 2 years post-randomisation using validated data on cancer occurrence, cancer staging, mortality and comorbidities.At 2 years, 127 lung cancers were detected in the study population (1.0%). In the intervention arm, 33 out of 56 (58.9%) lung cancers were diagnosed at stage III/IV compared with 52 out of 71 (73.2%) in the control arm. The hazard ratio for stage III/IV presentation was 0.64 (95% CI 0.41-0.99). There were nonsignificant differences in lung cancer and all-cause mortality after 2 years.ECLS compared EarlyCDT-Lung plus CT screening to standard clinical care (symptomatic presentation) and was not designed to assess the incremental contribution of the EarlyCDT-Lung test. The observation of a stage shift towards earlier-stage lung cancer diagnosis merits further investigations to evaluate whether the EarlyCDT-Lung test adds anything to the emerging standard of low-dose CT.

Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial.

BACKGROUND: Preoperative and perioperative aromatase inhibitor (POAI) therapy has the potential to improve outcomes in women with operable oestrogen receptor-positive primary breast cancer. It has also been suggested that tumour Ki67 values after 2 weeks (Ki672W) of POAI predicts individual patient outcome better than baseline Ki67 (Ki67B). The POETIC trial aimed to test these two hypotheses. METHODS: POETIC was an open-label, multicentre, parallel-group, randomised, phase 3 trial (done in 130 UK hospitals) in which postmenopausal women aged at least 50 years with WHO performance status 0-1 and hormone receptor-positive, operable breast cancer were randomly assigned (2:1) to POAI (letrozole 2·5 mg per day orally or anastrozole 1 mg per day orally) for 14 days before and following surgery or no POAI (control). Adjuvant treatment was given as per UK standard local practice. Randomisation was done centrally by computer-generated permuted block method (variable block size of six or nine) and was stratified by hospital. Treatment allocation was not masked. The primary endpoint was time to recurrence. A key second objective explored association between Ki67 (dichotomised at 10%) and disease outcomes. The primary analysis for clinical endpoints was by modified intention to treat (excluding patients who withdrew consent). For Ki67 biomarker association and endpoint analysis, the evaluable population included all randomly assigned patients who had paired Ki67 values available. This study is registered with ClinicalTrials.gov, NCT02338310; the European Clinical Trials database, EudraCT2007-003877-21; and the ISRCTN registry, ISRCTN63882543. Recruitment is complete and long-term follow-up is ongoing. FINDINGS: Between Oct 13, 2008, and April 16, 2014, 4480 women were recruited and randomly assigned to POAI (n=2976) or control (n=1504). On Feb 6, 2018, median follow-up was 62·9 months (IQR 58·1-74·1). 434 (10%) of 4480 women had a breast cancer recurrence (280 [9%] POAI; 154 [10%] control), hazard ratio 0·92 (95% CI 0·75-1·12); p=0·40 with the proportion free from breast cancer recurrence at 5 years of 91·0% (95% CI 89·9-92·0) for patients in the POAI group and 90·4% (88·7-91·9) in the control group. Within the POAI-treated HER2-negative subpopulation, 5-year recurrence risk in women with low Ki67B and Ki672W (low-low) was 4·3% (95% CI 2·9-6·3), 8·4% (6·8-10·5) with high Ki67B and low Ki672W (high-low) and 21·5% (17·1-27·0) with high Ki67B and Ki672W (high-high). Within the POAI-treated HER2-positive subpopulation, 5-year recurrence risk in the low-low group was 10·1% (95% CI 3·2-31·3), 7·7% (3·4-17·5) in the high-low group, and 15·7% (10·1-24·4) in the high-high group. The most commonly reported grade 3 adverse events were hot flushes (20 [1%] of 2801 patients in the POAI group vs six [<1%] of 1400 in the control group) and musculoskeletal pain (29 [1%] vs 13 [1%]). No treatment-related deaths were reported. INTERPRETATION: POAI has not been shown to improve treatment outcome, but can be used without detriment to help select appropriate adjuvant therapy based on tumour Ki67. Most patients with low Ki67B or low POAI-induced Ki672W do well with adjuvant standard endocrine therapy (giving consideration to clinical-pathological factors), whereas those whose POAI-induced Ki672W remains high might benefit from further adjuvant treatment or trials of new therapies. FUNDING: Cancer Research UK.

The clinical significance of oestrogen receptor expression in breast ductal carcinoma in situ.

BACKGROUND: Oestrogen receptor (ER) in invasive breast cancer (BC) predicts response to endocrine therapy (ET) and provides prognostic value. In this study, we investigated the value of ER expression in ductal carcinoma in situ (DCIS) in terms of outcome and the impact on ET decision. METHODS: In total, 643 pure DCIS, diagnosed at Nottingham University Hospitals, were assessed for ER. Clinicopathological data were correlated against ER status, together with assessment of recurrence rate. RESULTS: ER positivity was observed in 74% (475/643) of cases. ER positivity was associated with clinicopathological variables of good prognosis; however, outcome analysis revealed that ER status was not associated with local recurrence. In the intermediate- and high-grade ER-positive DCIS, 58% (11/19) and 63% (15/24) of the recurrences were invasive, respectively, comprising 7% and 6% of all ER-positive DCIS, respectively. Invasive recurrence in low-grade DCIS was infrequent (2%), and none of these patients died of BC. The ER status of the recurrent invasive tumours matched the primary DCIS ER status (94% in ipsilateral and 90% of contralateral recurrence). CONCLUSION: The strong correlation between DCIS and invasive recurrence ER status and the clinical impact of ET justify discussion of the use of ET in ER-positive DCIS treated by breast-conserving surgery. The excellent outcome of low-grade DCIS, which was almost always ER-positive, does not, in the opinion of authors, justify the use of risk-reducing ET. Therefore, the decision on ET for DCIS should be personalised and consider grade, ER status and other characteristics.

Correction: The clinical significance of oestrogen receptor expression in breast ductal carcinoma in situ.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Semiconducting few-layer PdSe2 and Pd2Se3: native point defects and contacts with native metallic Pd17Se15.

PdSe2 is a unique layered two-dimensional (2D) material with pentagonal structural motif and anisotropic properties. In addition, its strong interlayer interaction leads to new 2D form of the exfoliated monolayer, that is, Pd2Se3. Despite the increasing interest in these emerging 2D materials, the landscape of the native point defects, as a fundamental materials property, has not been revealed. In this work, we systematically investigate different types of defects in mono- and bi-layer PdSe2 and monolayer Pd2Se3. In contrast to the common expectation, Se vacancy is not the readily formed defect. Instead, Se-excess defects, such as SePd antisite and Se interstitial, are more likely to form over a majority of the allowed range of the atomic chemical potentials. Se-deficiency defect, Pd interstitial, is able to form under the Se-poor condition in bilayer PdSe2. The defect-mediated interlayer fusion model in the formation of monolayer Pd2Se3 from bilayer PdSe2 is reformulated. These dominant defects are found to stay in the neutral charge state, partly explaining the ambipolar behavior of the PdSe2 transistors. Finally, the stacked and lateral contacts between these few-layer semiconductors and the native Pd17Se15 metal are also studied. All these interfaces show p-type contact properties. This work reveals the important materials properties of few-layer PdSe2 and Pd2Se3 for the better development of new functional devices.

Modelling the enthalpy change and transition temperature dependence of the metal-insulator transition in pure and doped vanadium dioxide.

We compare various calculation methods to determine the electronic structures and energy differences of the phases of VO2. We show that density functional methods in the form of GGA+U are able to describe the enthalpy difference (latent heat) between the rutile and M1 phases of VO2, and the effect of doping on the transition temperature and on the band gap of the M1 phase. An enthalpy difference of ΔE0 = -44.2 meV per formula unit, similar to the experimental value, is obtained if the randomly oriented spins of the paramagnetic rutile phase are treated by a non-collinear spin density functional calculation. The predicted change in the transition temperature of VO2 for Ge, Si or Mg doping is calculated and is in good agreement with the experiment data.

Investigation of dissolution rate kinetics of bulk pharmaceutical feed streams within a stirred tank vessel and a twin screw extruder.

The introduction of continuous manufacturing of pharmaceuticals has highlighted the challenging area of continuous dissolution of solids for work ups to flow chemistry systems. In this study, the use of a 16 mm twin screw extruder (TSE) as a platform technology for solid feeds is investigated using four solid pharmaceutical ingredients (PI) in a mixture of water and IPA. In order for comparison, the same experiments were also carried out in a batch traditional stirred tank vessel (STV). The objectives of this work are to gain further scientific understanding on dissolution kinetics and to compare kinetics in both a batch and continuous system. The concentration of each PI during dissolution is monitored using an in-line UV-ATR probe, allowing the extraction of dissolution kinetics. Faster dissolution rates are achieved in the TSE than in the STV due to higher power dissipation generated by the aggressive shear mixing and thermal energy within the TSE. Complete dissolution of paracetamol is obtained within the residence time of the TSE; complete dissolution of benzoic acid and acetylsalicylic acid are achieved at higher barrel temperatures; however full dissolution of nicotinic acid is not achievable in the TSE under the experimental conditions.

Impact of aromatase inhibitor treatment on global gene expression and its association with antiproliferative response in ER+ breast cancer in postmenopausal patients.

BACKGROUND: Endocrine therapy reduces breast cancer mortality by 40%, but resistance remains a major clinical problem. In this study, we sought to investigate the impact of aromatase inhibitor (AI) therapy on gene expression and identify gene modules representing key biological pathways that relate to early AI therapy resistance. METHODS: Global gene expression was measured on pairs of core-cut biopsies taken at baseline and at surgery from 254 patients with ER-positive primary breast cancer randomised to receive 2-week presurgical AI (n = 198) or no presurgical treatment (control n = 56) from the POETIC trial. Data from the AI group was adjusted to eliminate artefactual process-related changes identified in the control group. The response was assessed by changes in the proliferation marker, Ki67. RESULTS: High baseline ESR1 expression associated with better AI response in HER2+ tumours but not HER2- tumours. In HER2- tumours, baseline expression of 48 genes associated with poor antiproliferative response (p < 0.005) including PERP and YWHAQ, the two most significant, and the transcription co-regulators (SAP130, HDAC4, and NCOA7) which were among the top 16 most significant. Baseline gene signature scores measuring cell proliferation, growth factor signalling (ERBB2-GS, RET/GDNF-GS, and IGF-1-GS), and immune activity (STAT1-GS) were significantly higher in poor AI responders. Two weeks of AI caused downregulation of genes involved in cell proliferation and ER signalling, as expected. Signature scores of E2F activation and TP53 dysfunction after 2-week AI were associated with poor AI response in both HER2- and HER2+ patients. CONCLUSIONS: There is a high degree of heterogeneity in adaptive mechanisms after as little as 2-week AI therapy; however, all appear to converge on cell cycle regulation. Our data support the evaluation of whether an E2F signatures after short-term exposure to AI may identify those patients most likely to benefit from the early addition of CDK4/6 inhibitors. TRIAL REGISTRATION: ISRCTN, ISRCTN63882543, registered on 18 December 2007.

Use of Terahertz-Raman Spectroscopy to Determine Solubility of the Crystalline Active Pharmaceutical Ingredient in Polymeric Matrices during Hot Melt Extrusion.

Polymer-based amorphous solid dispersions (ASDs) comprise one of the most promising formulation strategies devised to improve the oral bioavailability of poorly water-soluble drugs. Exploitation of such systems in marketed products has been limited because of poor understanding of physical stability. The internal disordered structure and increased free energy provide a thermodynamic driving force for phase separation and recrystallization, which can compromise therapeutic efficacy and limit product shelf life. A primary concern in the development of stable ASDs is the solubility of the drug in the polymeric carrier, but there is a scarcity of reliable analytical techniques for its determination. In this work, terahertz (THz) Raman spectroscopy was introduced as a novel empirical approach to determine the saturated solubility of crystalline active pharmaceutical ingredient (API) in polymeric matrices directly during hot melt extrusion. The solubility of a model compound, paracetamol, in two polymer systems, Affinisol 15LV (HPMC) and Plasdone S630 (copovidone), was determined by monitoring the API structural phase transitions from crystalline to amorphous as an excess of crystalline drug dissolved in the polymeric matrix. THz-Raman results enabled construction of solubility phase diagrams and highlighted significant differences in the solubilization capacity of the two polymer systems. The maximum stable API-load was 20 wt % for Affinisol 15LV and 40 wt % for Plasdone S630. Differential scanning calorimetry and XRPD studies corroborated these results. This approach has demonstrated a novel capability to provide real-time API-polymer phase equilibria data in a manufacturing relevant environment and promising potential to predict solid-state solubility and physical stability of ASDs.

Optical band gap of cross-linked, curved, and radical polyaromatic hydrocarbons.

In this work, the optical band gaps of polycyclic aromatic hydrocarbons (PAHs) crosslinked via an aliphatic bond, curved via pentagon integration and with radical character were computed using density functional theory. A variety of different functionals were benchmarked against optical band gaps (OBGs) measured by ultraviolet-visible spectroscopy with HSE06 being most accurate with a percentage error of 6% for a moderate basis set. Pericondensed aromatics with different symmetries were calculated with this improved functional providing new scaling relationships for the OBG versus size. Further calculations showed crosslinks cause a small decrease in the OBG of the monomers which saturates after 3-4 crosslinks. Curvature in PAHs was shown to increase the optical band gap due to the resulting change in hybridisation of the system, but this increase saturated at larger sizes. The increase in OBG between a flat PAH and a strained curved one was shown to be equivalent to a difference of several rings in size for pericondensed aromatic systems. The effect of σ-radicals on the optical band gap was also shown to be negligible, however, π-radicals were found to decrease the band gap by ∼0.5 eV. These findings have applications in understanding the molecular species involved in soot formation.

Cycled pulsing to mitigate thermal damage for multi-electrode irreversible electroporation therapy.

Purpose: This study evaluates the effects of various pulsing paradigms, on the irreversible electroporation (IRE) lesion, induced electric current, and temperature changes using a perfused porcine liver model. Materials and methods: A 4-monopolar electrode array delivered IRE therapy varying the pulse length and inter-pulse delay to six porcine mechanically perfused livers. Pulse paradigms included six forms of cycled pulsing schemes and the conventional pulsing scheme. Finite element models provided further insight into the effects of cycled pulsing on the temperature and thermal injury distribution. Results: 'Single pulse cycle with no interpulse delay' deposited maximum average energy (2.34 ± 0.35 kJ) and produced the largest ratio of thermally damaged tissue area and IRE ablation area from all other pulse schemes (18.22% ± 8.11, p < .0001 all pairwise comparisons). These compared favorably to the conventional algorithm (2.09 ± 0.37 kJ, 3.49% ± 2.20, p < .0001, all comparisons). Though no statistical significance was found between groups, the '5 pulse cycle, 0 s delay' pulse paradigm produced the largest average IRE ablation cross sectional area (11.81 ± 1.97 cm2), while conventional paradigm yielded an average of 8.90 ± 0.91 cm2. Finite element modeling indicated a '10 pulse cycle, 10 s delay' generated the least thermal tissue damage and '1 pulse cycle, 0 s delay' pulse cycle sequence the most (0.47 vs. 3.76 cm2), over a lengthier treatment time (16.5 vs. 6.67 minutes). Conclusions: Subdividing IRE pulses and adding delays throughout the treatment can reduce white tissue coagulation and electric current, while maintaining IRE treatment sizes.

Lung cancer screening: does pulmonary nodule detection affect a range of smoking behaviours?

BACKGROUND: Lung cancer screening can reduce lung cancer mortality by 20%. Screen-detected abnormalities may provide teachable moments for smoking cessation. This study assesses impact of pulmonary nodule detection on smoking behaviours within the first UK trial of a novel auto-antibody test, followed by chest x-ray and serial CT scanning for early detection of lung cancer (Early Cancer Detection Test-Lung Cancer Scotland Study). METHODS: Test-positive participants completed questionnaires on smoking behaviours at baseline, 1, 3 and 6 months. Logistic regression compared outcomes between nodule (n = 95) and normal CT groups (n = 174) at 3 and 6 months follow-up. RESULTS: No significant differences were found between the nodule and normal CT groups for any smoking behaviours and odds ratios comparing the nodule and normal CT groups did not vary significantly between 3 and 6 months. There was some evidence the nodule group were more likely to report significant others wanted them to stop smoking than the normal CT group (OR across 3- and 6-month time points: 3.04, 95% CI: 0.95, 9.73; P = 0.06). CONCLUSION: Pulmonary nodule detection during lung cancer screening has little impact on smoking behaviours. Further work should explore whether lung cancer screening can impact on perceived social pressure and promote smoking cessation.

Temporal variations of trace metals and a metalloid in temperate estuarine mangrove sediments.

Mangrove sediments are strong modulators of organic matter (OM) content and pollutant dynamics, acting both as sinks and sources of these components. This study aimed to assess temporal dynamics of OM within temperate mangrove sediments and their ability to sequester pollutants. Specifically, levels of trace metals (Fe, Cu, Zn, Pb, Cd) and a metalloid (As) were examined within mangrove and mudflat sediments located in a high-energy environment in Mangawhai Harbour Estuary, northern New Zealand. Sediment cores were collected from a mangrove stand and adjacent mudflats at three sediment depths during different months over a year. Variations in OM and elements were compared to rainfall and temperature patterns observed during the sampling period. All element concentrations, except for those of As, were significantly higher in mangrove compared to mudflat sediments during the entire sampling period. This is consistent with the well-reported ability of mangroves to trap suspended particles and OM. In addition, we observed a decreasing trend in trace metal concentrations with increasing sediment depth within mangrove habitat, which correlated well with decreasing OM content. Our results also suggested that most elements had different, but significant, temporal variations throughout the year, especially in mangrove sediments. Overall, the concentrations of Cu, Zn, Pb, Cd, and As in mangrove sediments increased during summer, whereas maximum levels of Fe and OM were observed in winter. This temporal pattern was determined to be related to OM and redox cycling as a result of changes in effluent input rates and physical/chemical environments during different seasons.

Extracellular matrix-based hydrogels obtained from human tissues: a work still in progress.

PURPOSE OF REVIEW: The current review summarizes contemporary decellularization and hydrogel manufacturing strategies in the field of tissue engineering and regenerative medicine. RECENT FINDINGS: Decellularized extracellular matrix (ECM) bioscaffolds are a valuable biomaterial that can be purposed into various forms of synthetic tissues such as hydrogels. ECM-based hydrogels can be of animal or human origin. The use of human tissues as a source for ECM hydrogels in the clinical setting is still in its infancy and current literature is scant and anecdotal, resulting in inconclusive results. SUMMARY: Thus far the methods used to obtain hydrogels from human tissues remains a work in progress. Gelation, the most complex technique in obtaining hydrogels, is challenging due to remarkable heterogeneity of the tissues secondary to interindividual variability. Age, sex, ethnicity, and preexisting conditions are factors that dramatically undermine the technical feasibility of the gelation process. This is contrasted with animals whose well defined anatomical and histological characteristics have been selectively bred for the goal of manufacturing hydrogels.