Using diffusion MRI data acquired with ultra-high gradient strength to improve tractography in routine-quality data.

The development of scanners with ultra-high gradient strength, spearheaded by the Human Connectome Project, has led to dramatic improvements in the spatial, angular, and diffusion resolution that is feasible for in vivo diffusion MRI acquisitions. The improved quality of the data can be exploited to achieve higher accuracy in the inference of both microstructural and macrostructural anatomy. However, such high-quality data can only be acquired on a handful of Connectom MRI scanners worldwide, while remaining prohibitive in clinical settings because of the constraints imposed by hardware and scanning time. In this study, we first update the classical protocols for tractography-based, manual annotation of major white-matter pathways, to adapt them to the much greater volume and variability of the streamlines that can be produced from today's state-of-the-art diffusion MRI data. We then use these protocols to annotate 42 major pathways manually in data from a Connectom scanner. Finally, we show that, when we use these manually annotated pathways as training data for global probabilistic tractography with anatomical neighborhood priors, we can perform highly accurate, automated reconstruction of the same pathways in much lower-quality, more widely available diffusion MRI data. The outcomes of this work include both a new, comprehensive atlas of WM pathways from Connectom data, and an updated version of our tractography toolbox, TRActs Constrained by UnderLying Anatomy (TRACULA), which is trained on data from this atlas. Both the atlas and TRACULA are distributed publicly as part of FreeSurfer. We present the first comprehensive comparison of TRACULA to the more conventional, multi-region-of-interest approach to automated tractography, and the first demonstration of training TRACULA on high-quality, Connectom data to benefit studies that use more modest acquisition protocols.

Resource-efficient frequency conversion for quantum networks via sequential four-wave mixing.

We report a resource-efficient scheme in which a single pump laser was used to achieve frequency conversion by Bragg-scattering four-wave mixing in a photonic crystal fiber. We demonstrate bidirectional conversion of coherent light between Sr+2P1/2→2D3/2 emission wavelength at 1092 nm and the telecommunication C band with conversion efficiencies of 4.2% and 37% for up- and down-conversion, respectively. We discuss how the scheme may be viably scaled to meet the temporal, spectral, and polarization stability requirements of a hybrid light-matter quantum network.

Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial.

BACKGROUND: STAMPEDE has previously reported that the use of upfront docetaxel improved overall survival (OS) for metastatic hormone naïve prostate cancer patients starting long-term androgen deprivation therapy. We report on long-term outcomes stratified by metastatic burden for M1 patients. METHODS: We randomly allocated patients in 2 : 1 ratio to standard-of-care (SOC; control group) or SOC + docetaxel. Metastatic disease burden was categorised using retrospectively-collected baseline staging scans where available. Analysis used Cox regression models, adjusted for stratification factors, with emphasis on restricted mean survival time where hazards were non-proportional. RESULTS: Between 05 October 2005 and 31 March 2013, 1086 M1 patients were randomised to receive SOC (n = 724) or SOC + docetaxel (n = 362). Metastatic burden was assessable for 830/1086 (76%) patients; 362 (44%) had low and 468 (56%) high metastatic burden. Median follow-up was 78.2 months. There were 494 deaths on SOC (41% more than the previous report). There was good evidence of benefit of docetaxel over SOC on OS (HR = 0.81, 95% CI 0.69-0.95, P = 0.009) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P = 0.827). Analysis of other outcomes found evidence of benefit for docetaxel over SOC in failure-free survival (HR = 0.66, 95% CI 0.57-0.76, P < 0.001) and progression-free survival (HR = 0.69, 95% CI 0.59-0.81, P < 0.001) with no evidence of heterogeneity of docetaxel effect between metastatic burden sub-groups (interaction P > 0.5 in each case). There was no evidence that docetaxel resulted in late toxicity compared with SOC: after 1 year, G3-5 toxicity was reported for 28% SOC and 27% docetaxel (in patients still on follow-up at 1 year without prior progression). CONCLUSIONS: The clinically significant benefit in survival for upfront docetaxel persists at longer follow-up, with no evidence that benefit differed by metastatic burden. We advocate that upfront docetaxel is considered for metastatic hormone naïve prostate cancer patients regardless of metastatic burden.

Long-term systemic lupus erythematosus disease control after allogeneic bone marrow transplantation.

Systemic lupus erythematosus (SLE), a disorder of the immune system, is potentially curable by allogeneic bone marrow transplantation (alloBMT). Until recently, alloBMT was limited by donor availability and toxicity. Reduced intensity conditioning (RIC) combined with post-transplantation cyclophosphamide (PTCy) has improved the availability and safety of alloBMT permitting its exploration in severe-refractory autoimmune illnesses. We report the six-year follow-up of a young female whose refractory SLE-associated nephrosis resolved after RIC alloBMT with PTCy.

A randomised, phase II study of nintedanib or sunitinib in previously untreated patients with advanced renal cell cancer: 3-year results.

BACKGROUND: This exploratory study evaluated the safety/efficacy of nintedanib or sunitinib as first-line therapy in patients with advanced renal cell carcinoma (RCC). METHODS: Ninety-six patients were randomised (2:1) to either nintedanib (200 mg twice daily) or sunitinib (50 mg kg(-1) once daily (4 weeks on treatment; 2 weeks off)). Primary endpoint was progression-free survival (PFS) at 9 months. P-values reported are descriptive only; the study was not powered for such comparisons. RESULTS: Progression-free survival at 9 months was comparable between nintedanib and sunitinib (43.1% vs 45.2%, respectively; P=0.85). Median PFS was 8.4 months in each group (hazard ratio (HR), 1.12; 95% confidence interval (CI): 0.70-1.80; P=0.64). Median overall survival was 20.4 and 21.2 months for nintedanib and sunitinib, respectively (HR, 0.92; 95% CI: 0.54-1.56; P=0.76). Overall incidence of any grade adverse events (AEs) was comparable (90.6% vs 93.8%); AEs grade ⩾ 3 were lower with nintedanib than sunitinib (48.4% vs 59.4%). Nintedanib was associated with lower incidences of some AEs typical of antiangiogenic tyrosine kinase inhibitors (TKIs): hypertension, hypothyroidism, hand-foot syndrome, cardiac disorders and haematological abnormalities. CONCLUSIONS: In patients with advanced RCC, nintedanib has promising efficacy and similar tolerability to sunitinib, and a manageable safety profile with fewer TKI-associated AEs.

AZD3514, an oral selective androgen receptor down-regulator in patients with castration-resistant prostate cancer - results of two parallel first-in-human phase I studies.

BACKGROUND: AZD3514 is a first-in-class, orally bio-available, androgen-dependent and -independent androgen receptor inhibitor and selective androgen-receptor down-regulator (SARD). METHODS: In study 1 and 2, castration-resistant prostate cancer (CRPC) patients (pts) were initially recruited into a once daily (QD) oral schedule (A). In study 1, pharmacokinetic assessments led to twice daily (BID) dosing (schedule B) to increase exposure. Study 2 explored a once daily schedule. RESULTS: In study 1, 49 pts were treated with escalating doses of AZD3514 (A 35 pts, B 14 pts). Starting doses were 100 mg (A) and 1000 mg (B). The AZD3514 formulation was switched from capsules to tablets at 1000 mg QD. 2000 mg BID was considered non-tolerable due to grade (G) 2 toxicities (nausea [N], vomiting [V]). No adverse events (AEs) met the dose-limiting toxicity (DLT) definition. Thirteen pts received AZD3514 in study 2, with starting doses of 250 mg QD. The most frequent drug-related AEs were N: G1/2 in 55/70 pts (79 %); G3 in 1 pt (1.4 %); & V: G1/2 in 34/70 pts (49 %) & G3 in 1 pt (1.4 %). PSA declines (≥50 %) were documented in 9/70 patients (13 %). Objective soft tissue responses per RECIST1.1 were observed in 4/24 (17 %) pts in study 1. CONCLUSION: AZD3514 has moderate anti-tumour activity in pts with advanced CRPC but with significant levels of nausea and vomiting. However, anti-tumour activity as judged by significant PSA declines, objective responses and durable disease stabilisations, provides the rationale for future development of SARD compounds.

High-throughput synchrotron X-ray diffraction for combinatorial phase mapping.

Discovery of new materials drives the deployment of new technologies. Complex technological requirements demand precisely tailored material functionalities, and materials scientists are driven to search for these new materials in compositionally complex and often non-equilibrium spaces containing three, four or more elements. The phase behavior of these high-order composition spaces is mostly unknown and unexplored. High-throughput methods can offer strategies for efficiently searching complex and multi-dimensional material genomes for these much needed new materials and can also suggest a processing pathway for synthesizing them. However, high-throughput structural characterization is still relatively under-developed for rapid material discovery. Here, a synchrotron X-ray diffraction and fluorescence experiment for rapid measurement of both X-ray powder patterns and compositions for an array of samples in a material library is presented. The experiment is capable of measuring more than 5000 samples per day, as demonstrated by the acquisition of high-quality powder patterns in a bismuth-vanadium-iron oxide composition library. A detailed discussion of the scattering geometry and its ability to be tailored for different material systems is provided, with specific attention given to the characterization of fiber textured thin films. The described prototype facility is capable of meeting the structural characterization needs for the first generation of high-throughput material genomic searches.

Geographic differences in vertical connectivity in the Caribbean coral Montastraea cavernosa despite high levels of horizontal connectivity at shallow depths.

The deep reef refugia hypothesis proposes that deep reefs can act as local recruitment sources for shallow reefs following disturbance. To test this hypothesis, nine polymorphic DNA microsatellite loci were developed and used to assess vertical connectivity in 583 coral colonies of the Caribbean depth-generalist coral Montastraea cavernosa. Samples were collected from three depth zones (≤10, 15-20 and ≥25 m) at sites in Florida (within the Upper Keys, Lower Keys and Dry Tortugas), Bermuda, and the U.S. Virgin Islands. Migration rates were estimated to determine the probability of coral larval migration from shallow to deep and from deep to shallow. Finally, algal symbiont (Symbiodinium spp.) diversity and distribution were assessed in a subset of corals to test whether symbiont depth zonation might indicate limited vertical connectivity. Overall, analyses revealed significant genetic differentiation by depth in Florida, but not in Bermuda or the U.S. Virgin Islands, despite high levels of horizontal connectivity between these geographic locations at shallow depths. Within Florida, greater vertical connectivity was observed in the Dry Tortugas compared to the Lower or Upper Keys. However, at all sites, and regardless of the extent of vertical connectivity, migration occurred asymmetrically, with greater likelihood of migration from shallow to intermediate/deep habitats. Finally, most colonies hosted a single Symbiodinium type (C3), ruling out symbiont depth zonation of the dominant symbiont type as a structuring factor. Together, these findings suggest that the potential for shallow reefs to recover from deep-water refugia in M. cavernosa is location-specific, varying among and within geographic locations likely as a consequence of local hydrology.

Communication and professionalism skills of a new graduate: the expectations and experiences of dental foundation trainers.

AIM: The aim of this study was to investigate dental foundation year 1 (DF1) trainers' expectations of the dental graduate specifically in relation to non-clinical (professionalism and communication) skills and to explore whether these expectations were being met. METHOD: In the UK, dental graduates undertake 1 year of foundation training prior to being permitted to undertake NHS practice. An online survey was distributed to DF1 trainers via all 11 English deaneries and the Northern Ireland deanery. Demographic information and a general view of trainers' expectations of a new trainee were collected. Specific questions relating to six generic trainee problems were followed by 11 ability statements where trainers indicated their expectation of a trainee's ability to perform the skill on a 5-point scale (on own with confidence-unable to undertake). Statements were repeated and trainers were required to respond using the same scale in relation to experience of their current trainee. RESULTS: Five hundred and ten (53%) trainers completed the questionnaire with no missing data. Expectations were high with almost 50% of trainers expecting a new graduate to manage a full list of patients on their own. Experience of new graduates did not always match these expectations. Of concern was the ability to 'keep accurate patient records' and 'self-reflection and knowing when to seek help', where a small proportion of trainers experienced difficulties. CONCLUSIONS: Trainers' expectation and experience in relation to non-clinical skills of a new graduate were investigated. Although they had high expectations, the majority reported only minor problems overall. There were a few areas where concern was raised.

Expression and prognostic significance of Src family members in renal clear cell carcinoma.

BACKGROUND: The aim of this study was to determine whether Src family kinases (SFK) are expressed in renal cell cancer and to assess their prognostic significance. METHODS: mRNA expression levels were investigated for the 8 SFK members by quantitative real-time PCR in 19 clear cell cancer tissue samples. Immunohistochemical staining was utilised to assess expression of Src kinase, dephosphorylated Src kinase at Y(530) (SrcY(530)), phosphorylated Src at Y(419) (SrcY(419)) and the downstream focal adhesion kinase (FAK) marker at the Y(861) site (FAK Y(861)) in a cohort of 57 clear cell renal cancer specimens. Expression was assessed using the weighted histoscore method. RESULTS: Src, Lyn, Hck, Fgr and Fyn were the most highly expressed in renal cancer. All members were more highly expressed in T2 disease, and furthermore expression levels between T2 and T3 disease showed a significant decrease for Lck, Lyn, Fyn, Blk and Yes (P=0.032). Assessment of membrane, cytoplasm and nuclear expression of Src kinase, SrcY(530) and SrcY(419) were not significantly associated with cancer-specific survival. High expression of cytoplasmic FAK Y(861) was associated with decreased cancer-specific survival (P=0.001). On multivariate analysis, cytoplasmic FAK Y(861) was independently associated with cancer-specific survival (hazard ratio 3.35, 95% CI 1.40-7.98, P=0.006). CONCLUSION: We have reported that all SFK members are expressed in renal cell carcinoma. The SFK members had their highest levels of expression before the disease no longer being organ confined. We hypothesise that these SFK members are upregulated before the cancer spreading out-with the organ and given that Src itself is not associated with cancer-specific survival but the presence of FAK Y(861), a downstream marker for SFK member activity is associated with decreased cancer-specific survival, we hypothesise that another SFK member is associated with decreased cancer-specific survival in renal cell cancer.

Space-time resolved simulation of femtosecond nonlinear light-matter interactions using a holistic quantum atomic model: application to near-threshold harmonics.

We introduce a new computational approach for femtosecond pulse propagation in the transparency region of gases that permits full resolution in three space dimensions plus time while fully incorporating quantum coherent effects such as high-harmonic generation and strong-field ionization in a holistic fashion. This is achieved by utilizing a one-dimensional model atom with a delta-function potential which allows for a closed-form solution for the nonlinear optical response due to ground-state to continuum transitions. It side-steps evaluation of the wave function, and offers more than one hundred-fold reduction in computation time in comparison to direct solution of the atomic Schrödinger equation. To illustrate the capability of our new computational approach, we apply it to the example of near-threshold harmonic generation in Xenon, and we also present a qualitative comparison between our model and results from an in-house experiment on extreme ultraviolet generation in a femtosecond enhancement cavity.

The influence of seat backrest angle on human performance during whole-body vibration.

This study investigated the effects of reclined backrest angles on cognitive and psycho-motor tasks during exposure to vertical whole-body vibration. Twenty participants were each exposed to three test stimuli of vertical vibration: 2-8 Hz; 8-14 Hz and 14-20 Hz, plus a stationary control condition whilst seated on a vibration platform at five backrest angles: 0° (recumbent, supine) to 90° (upright). The vibration magnitude was 2.0 ms(-2) root-mean-square. The participants were seated at one of the backrest angles and exposed to each of the three vibration stimuli while performing a tracking and choice reaction time tasks; then they completed the NASA-TLX workload scales. Apart from 22.5° seat backrest angle for the tracking task, backrest angle did not adversely affect the performance during vibration. However, participants required increased effort to maintain performance during vibration relative to the stationary condition. These results suggest that undertaking tasks in an environment with vibration could increase workload and risk earlier onset of fatigue. PRACTITIONER SUMMARY: Current vibration standards provide guidance for assessing exposures for seated, standing and recumbent positions, but not for semi-recumbent postures. This paper reports new experimental data systematically investigating the effect of backrest angle on human performance. It demonstrates how workload is elevated with whole-body vibration, without getting affected by backrest angle.

Cancer Trial Impact: Understanding Implementation of the Short Course Oncology Treatment (SCOT) Trial Findings in colorectal cancer at a National Level.

AIMS: The Short Course Oncology Treatment (SCOT) trial indicated that 3 months of adjuvant doublet chemotherapy was non-inferior to 6 months of treatment for patients with colorectal cancer, with considerably less toxicity. The SCOT trial results were disseminated in June 2017. The aim of this study was to understand if SCOT trial findings were implemented in Scotland. MATERIALS AND METHODS: A retrospective analysis was carried out on a dataset derived from a source population of 5.4 million people. Eligible patients were those with stage II or III colorectal cancer who received adjuvant chemotherapy. Logistic regression was applied to understand the extent of practice change to a 3-month adjuvant chemotherapy duration after the SCOT trial results were disseminated. Interrupted time series analysis was used to visualise differences in prescribing trends before and after June 2017 for the overall cohort, and by SCOT trial eligibility. RESULTS: In total, 2310 patients were included in the study; 1957 and 353 treated pre- and post-June 2017, respectively. The median treatment duration decreased from 21 weeks (interquartile range 14-24) prior to June 2017 to 12 weeks (interquartile range 12-21 weeks) after June 2017 (P < 0.001). The proportion of patients receiving over 3 months of adjuvant treatment decreased from 75% to 42% (P < 0.001). This change was most noticeable for patients who met the SCOT trial eligibility criteria, and specifically for those with low-risk stage III disease and those treated with capecitabine and oxaliplatin (CAPOX). Although practice change occurred in all locations, there were differences between regions that could be explained by pre-SCOT trial prescribing trends. DISCUSSION: A significant change in chemotherapy prescribing occurred after dissemination of the SCOT trial results. National, real-world data can be used to capture the extent of implementation of clinical trial results. In this case, implementation was aligned with clinical trial subgroup findings. This type of analysis could be conducted to evaluate the impact of other clinical trials.

Low noise erbium fiber fs frequency comb based on a tapered-fiber carbon nanotube design.

We report on a low noise all-fiber erbium fs frequency comb based on a simple and robust tapered-fiber carbon nanotube (tf-CNT) design. We mitigate dominant noise sources to show that the free-running linewidth of the carrier-envelope offset frequency (fceo) can be comparable to the best reported performance to date for fiber-based frequency combs. A free-running fceo linewidth of ~20 kHz is demonstrated, corresponding to an improvement of ~30 times over previous work based on a CNT mode-locked fiber laser [Opt. Express 18, 1667 (2010)]. We also demonstrate the use of an acousto-optic modulator external to the laser cavity to stabilize fceo, enabling a 300 kHz feedback control bandwidth. The offset frequency is phase-locked with an in-loop integrated phase noise of ~0.8 rad from 10Hz to 400kHz. We show a resolution-limited linewidth of ~1 Hz, demonstrating over 90% of the carrier power within the coherent fceo signal. The results demonstrate that the relatively simple tf-CNT fiber laser design can provide a compact, robust and high-performance fs frequency comb.

Intracavity ionization and pulse formation in femtosecond enhancement cavities.

We experimentally and numerically investigate the intracavity ionization of a dilute gas target by an ultrashort pulse inside a femtosecond enhancement cavity. Numerical simulations detail how the dynamic ionization of the gas target limits the achievable peak intensity of the evolving intracavity pulse beyond that of linear cavity losses, setting a constraint on the strength of the nonlinear interaction that can be sustained in such optical cavities. Experimental measurements combined with numerical simulations predict ionization levels in a femtosecond enhancement cavity for the first time. We demonstrate how the resonant response of the femtosecond enhancement cavity can itself be used as a sensitive probe of optical nonlinearities at high intensities.

Selective radiosensitization of p53-deficient cells by caffeine-mediated activation of p34cdc2 kinase.

The induction of tumor cell death by anticancer therapy results from a genetic program of autonomous cell death termed apoptosis. Because the p53 tumor suppressor gene is a critical component for induction of apoptosis in response to DNA damage, its inactivation in cancers may be responsible for their resistance to genotoxic anticancer agents. The cellular response to DNA damage involves a cell-cycle arrest at both the G1/S and G2/M transitions; these checkpoints maintain viability by preventing the replication or segregation of damaged DNA. The arrest at the G1 checkpoint is mediated by p53-dependent induction of p21WAF1/CIP1, whereas the G2 arrest involves inactivation of p34cdc2 kinase. Following DNA damage, p53-deficient cells fail to arrest at G1 and accumulate at the G2/M transition. We demonstrate that abrogation of G2 arrest by caffeine-mediated activation of p34cdc2 kinase results in the selective sensitization of p53-deficient primary and tumor cells to irradiation-induced apoptosis. These data suggest that pharmacologic activation of p34cdc2 kinase may be a useful therapeutic strategy for circumventing the resistance of p53-deficient cancers to genotoxic anticancer agents.

Fermentative volatile fatty acid production and recovery from grass using a novel combination of solids separation, pervaporation, and electrodialysis technologies.

A novel combination of solids screening, centrifugation, microfiltration, pervaporation, and electrodialysis were used for the targeted and exclusive recovery of volatile fatty acids (VFAs) from an 80L bioreactor. The bioreactor was continually-fed with grass waste, containing 40gL-1 total solids, over three, seven-day, hydraulic retention times. A VFA solution with a concentration up to 4,500 mgL-1 was recovered. VFA yields were also increased from 707 to 875 mg of VFA per gram of volatile solids by alleviating end-product inhibition. Both these accomplishments are significant step-changes in adding value to waste, and increased substrate utilisation rates will be attractive from a waste remediation perspective.

Immunologic recovery following autologous stem-cell transplantation with pre- and posttransplantation rituximab for low-grade or mantle cell lymphoma.

BACKGROUND: Rituximab may improve transplant outcomes but may delay immunologic recovery. PATIENTS AND METHODS: Seventy-seven patients with low-grade or mantle cell lymphoma received autologous stem-cell transplantation (ASCT) on a phase II study. Rituximab 375 mg/m(2) was administered 3 days before mobilization-dose cyclophosphamide, then weekly for four doses after count recovery from ASCT. Immune reconstitution was assessed. RESULTS: Sixty percent of transplants occurred in first remission. Actuarial event-free survival (EFS) and overall survival (OS) were 60% and 73%, respectively, at 5 years, with 7.2-year median follow-up for OS in surviving patients. Median EFS was 8.3 years. Older age and transformed lymphomas were independently associated with inferior EFS, whereas day 60 lymphocyte counts did not predict EFS or late infections. Early and late transplant-related mortality was 1% and 8%, with secondary leukemia in two patients. B-cell counts recovered by 1-2 years; however, the median IgG level remained low at 2 years. Late-onset idiopathic neutropenia, generally inconsequential, was noted in 43%. CONCLUSION: ASCT with rituximab can produce durable remissions on follow-up out to 10 years. Major infections do not appear to be significantly increased or to be predicted by immune monitoring.

High power femtosecond source near 1 micron based on an all-fiber Er-doped mode-locked laser.

We report the design and performance of a high power femtosecond laser source near 1 micron wavelength which is generated from an octave-spanning supercontinuum (SC) pumped by an Er-doped mode-locked laser. The laser system delivers >5W average power at 35MHz repetition rate and 135 fs pulse duration.