Phase Space Reconstruction from Accelerator Beam Measurements Using Neural Networks and Differentiable Simulations.

Characterizing the phase space distribution of particle beams in accelerators is a central part of understanding beam dynamics and improving accelerator performance. However, conventional analysis methods either use simplifying assumptions or require specialized diagnostics to infer high-dimensional (>2D) beam properties. In this Letter, we introduce a general-purpose algorithm that combines neural networks with differentiable particle tracking to efficiently reconstruct high-dimensional phase space distributions without using specialized beam diagnostics or beam manipulations. We demonstrate that our algorithm accurately reconstructs detailed 4D phase space distributions with corresponding confidence intervals in both simulation and experiment using a limited number of measurements from a single focusing quadrupole and diagnostic screen. This technique allows for the measurement of multiple correlated phase spaces simultaneously, which will enable simplified 6D phase space distribution reconstructions in the future.

Differentiable Preisach Modeling for Characterization and Optimization of Particle Accelerator Systems with Hysteresis.

Future improvements in particle accelerator performance are predicated on increasingly accurate online modeling of accelerators. Hysteresis effects in magnetic, mechanical, and material components of accelerators are often neglected in online accelerator models used to inform control algorithms, even though reproducibility errors from systems exhibiting hysteresis are not negligible in high precision accelerators. In this Letter, we combine the classical Preisach model of hysteresis with machine learning techniques to efficiently create nonparametric, high-fidelity models of arbitrary systems exhibiting hysteresis. We experimentally demonstrate how these methods can be used in situ, where a hysteresis model of an accelerator magnet is combined with a Bayesian statistical model of the beam response, allowing characterization of magnetic hysteresis solely from beam-based measurements. Finally, we explore how using these joint hysteresis-Bayesian statistical models allows us to overcome optimization performance limitations that arise when hysteresis effects are ignored.

Recovering the phase and amplitude of X-ray FEL pulses using neural networks and differentiable models.

Dynamics experiments are an important use-case for X-ray free-electron lasers (XFELs), but time-domain measurements of the X-ray pulses themselves remain a challenge. Shot-by-shot X-ray diagnostics could enable a new class of simpler and potentially higher-resolution pump-probe experiments. Here, we report training neural networks to combine low-resolution measurements in both the time and frequency domains to recover X-ray pulses at high-resolution. Critically, we also recover the phase, opening the door to coherent-control experiments with XFELs. The model-based generative neural-network architecture can be trained directly on unlabeled experimental data and is fast enough for real-time analysis on the new generation of MHz XFELs.

Invasive and in situ squamous cell carcinoma of the skin: a nationwide study in Iceland.

BACKGROUND: The worldwide incidence of cutaneous squamous cell carcinoma (cSCC) is increasing. OBJECTIVES: To evaluate the tumour burden of in situ and invasive cSCC in Iceland, where the population is exposed to limited ultraviolet radiation. METHODS: This whole-population study used the Icelandic Cancer Registry, which contains records of all in situ and invasive cSCC cases from 1981 to 2017. Incidence of cSCC was evaluated according to age, anatomical location, residence and multiplicity, and trends were assessed using joinpoint analysis. Age-standardized rates (WSR) and age-specific incidence rates per 100 000 person-years were calculated, along with cumulative and lifetime risks. RESULTS: Between 1981 and 2017, in situ cSCC WSR increased from 1·2 to 19·1 for men and from 2·0 to 22·3 for women. Invasive cSCC WSR rose from 4·6 to 14 for men and from 0·3 to 13·2 for women. The average number of in situ cSCC lesions was 1·71 per woman and 1·39 per man. Women developed more in situ cSCCs than invasive cSCCs in almost all anatomical locations, whereas men developed more invasive cSCCs, mostly on the head and neck. The rates of in situ cSCC were higher in Reykjavik compared with rural areas. Furthermore, women more commonly developed multiple in situ lesions. For lip cSCCs, invasive lesions occurred more frequently than in situ lesions among both sexes. Joinpoint analysis showed that in situ cSCC in women exhibited the most rapid incidence increase. CONCLUSIONS: cSCC has become an increasingly significant public health problem in Iceland. Tanning bed use and travelling abroad may contribute to skin cancer development. Public health efforts are needed to stem the behaviours leading to this rapid rise in cSCC.

Bayesian Optimization of a Free-Electron Laser.

The Linac coherent light source x-ray free-electron laser is a complex scientific apparatus which changes configurations multiple times per day, necessitating fast tuning strategies to reduce setup time for successive experiments. To this end, we employ a Bayesian approach to maximizing x-ray laser pulse energy by controlling groups of quadrupole magnets. A Gaussian process model provides probabilistic predictions for the machine response with respect to control parameters, enabling a balance of exploration and exploitation in the search for the global optimum. We show that the model parameters can be learned from archived scans, and correlations between devices can be extracted from the beam transport. The result is a sample-efficient optimization routine, combining both historical data and knowledge of accelerator physics to significantly outperform existing optimizers.

Basal cell carcinoma: an emerging epidemic in women in Iceland.

BACKGROUND: An epidemic of basal cell carcinoma (BCC) has led to a significant healthcare burden in white populations. OBJECTIVES: To provide an update on incidence rates and tumour burden in an unselected, geographically isolated population that is exposed to a low level of ultraviolet radiation. METHODS: This was a whole-population study using a cancer registry containing records of all cases of BCC in 1981-2017. We assessed BCC incidence according to age, residence and multiplicity and assessed trends using join-point analysis. Age-standardized and age-specific incidence rates were calculated along with cumulative and lifetime risks. RESULTS: During the study period, the age-standardized incidence rates increased from 25·7 to 59·9 for men, and from 22·2 to 83·1 for women (per 100 000). Compared with the single-tumour burden, the total tumour burden in the population was 1·72 times higher when accounting for multiplicity. At the beginning of the study period, the world-standardized rates in men and women were similar, but by the end of the study period the rates were 39% higher in women (83·1 per 100 000, 95% confidence interval 77·9-88·3) than in men (59·9 per 100 000, 95% confidence interval 55·6-64·2). This increase was most prominent in women on sites that are normally not exposed to ultraviolet radiation in Iceland: the trunk and legs. CONCLUSIONS: This is the only reported population in which the incidence of BCC is significantly higher in women than in men. The period of notable increase in BCC lesions correlates with the period of an increase in tanning beds and travel popularity. The high multiplicity rates suggest that the total tumour burden worldwide might be higher than previously thought. What is already known about this topic? Basal cell carcinoma (BCC) is becoming an increasing healthcare burden worldwide, especially in white populations. Recent population studies have reported a rapid increase in incidence among younger individuals, especially women. What does this study add? Iceland is the only reported population in which the incidence of BCC is significantly higher in women than in men, and there does not seem to be a clear relationship between latitude and BCC incidence in Europe. Men might be comparatively protected in the northern low-ultraviolet environment, with tanning beds and travel abroad likely playing important roles in the observed incidence increase, especially in women. The high multiplicity rates suggest that the total tumour burden worldwide might be higher than previously thought. Linked Comment: Pandeya. Br J Dermatol 2020; 183:799-800.

Electron Ghost Imaging.

In this Letter we report a demonstration of electron ghost imaging. A digital micromirror device directly modulates the photocathode drive laser to control the transverse distribution of a relativistic electron beam incident on a sample. Correlating the structured illumination pattern to the total sample transmission then retrieves the target image, avoiding the need for a pixelated detector. In our example, we use a compressed sensing framework to improve the reconstruction quality and reduce the number of shots compared to raster scanning a small beam across the target. Compressed electron ghost imaging can reduce both acquisition time and sample damage in experiments for which spatially resolved detectors are unavailable (e.g., spectroscopy) or in which the experimental architecture precludes full frame direct imaging.

Imaging Molecular Motion: Femtosecond X-Ray Scattering of an Electrocyclic Chemical Reaction.

Structural rearrangements within single molecules occur on ultrafast time scales. Many aspects of molecular dynamics, such as the energy flow through excited states, have been studied using spectroscopic techniques, yet the goal to watch molecules evolve their geometrical structure in real time remains challenging. By mapping nuclear motions using femtosecond x-ray pulses, we have created real-space representations of the evolving dynamics during a well-known chemical reaction and show a series of time-sorted structural snapshots produced by ultrafast time-resolved hard x-ray scattering. A computational analysis optimally matches the series of scattering patterns produced by the x rays to a multitude of potential reaction paths. In so doing, we have made a critical step toward the goal of viewing chemical reactions on femtosecond time scales, opening a new direction in studies of ultrafast chemical reactions in the gas phase.

Experimental demonstration of a soft x-ray self-seeded free-electron laser.

The Linac Coherent Light Source has added a self-seeding capability to the soft x-ray range using a grating monochromator system. We report the demonstration of soft x-ray self-seeding with a measured resolving power of 2000-5000, wavelength stability of 10(-4), and an increase in peak brightness by a factor of 2-5 across the photon energy range of 500-1000 eV. By avoiding the need for a monochromator at the experimental station, the self-seeded beam can deliver as much as 50-fold higher brightness to users.

Associations of non-melanoma skin cancer and melanoma, extra-cutaneous cancers and smoking in adults: a US population-based study.

BACKGROUND: Non-melanoma skin cancer (NMSC) and melanoma are common malignancies in the US and may be associated with other types of cancer. OBJECTIVES: We sought to determine whether NMSC and melanoma are associated with extra-cutaneous cancers and identify modifiable risk factors for such an association. METHODS: We analysed data from 447,801 adult participants in the 1997-2011 National Health Interview Surveys. Survey logistic regression models were constructed that accounted for the complex sample weights. History of NMSC, melanoma and 27 primary extra-cutaneous cancers was assessed. RESULTS: NMSC was associated with increased odds of one (multinomial survey logistic regression, unadjusted odds ratio [95% CI]: 2.43 [2.20-2.68]) or multiple (2.94 [2.21-3.92]) extra-cutaneous malignancies. Melanoma was also associated with increased odds of one (3.25 [2.70-3.90]) or multiple (6.11 [4.34-8.61]) extra-cutaneous malignancies. Extra-cutaneous cancers were more common in younger patients (ages 18-39 and 40-49 years) and Caucasians with NMSC or melanoma (P < 0.0001). Smokers with a history of NMSC or melanoma had even higher odds of extra-cutaneous malignancy at ages 18-39 and 40-49 years compared to smokers without NMSC or melanoma (P < 0.0001). History of NMSC was associated with higher odds of malignancies of the bladder, brain, breast, colon, oesophagus, kidney, lung, lymphoma, melanoma, prostate, soft tissue, throat/pharynx, thyroid and uterus. Melanoma was associated with malignancies of the bladder, breast, colon, kidney, lung, pancreas, prostate, soft tissue, throat/pharynx, thyroid and uterus. The prevalence of extra-cutaneous cancers increased between 1997 and 2011 in all subjects (4.51% and 5.73%, P < 0.0001), with even higher rates of increase in those with history of NMSC or melanoma. CONCLUSIONS: Patients with history of NMSC and melanoma have increased odds of developing extra-cutaneous cancers, especially those with younger age and smoking history.

Microbunched electron cooling for high-energy hadron beams.

Electron and stochastic cooling are proven methods for cooling low-energy hadron beams, but at present there is no way of cooling hadrons as they near the TeV scale. In the 1980s, Derbenev suggested that electron instabilities, such as free-electron lasers, could create collective space charge fields strong enough to correct the hadron energies. This Letter presents a variation on Derbenev's electron cooling scheme using the microbunching instability as the amplifier. The large bandwidth of the instability allows for faster cooling of high-density beams. A simple analytical model illustrates the cooling mechanism, and simulations show cooling rates for realistic parameters of the Large Hadron Collider.

Blinded vs. unblinded peer review of manuscripts submitted to a dermatology journal: a randomized multi-rater study.

BACKGROUND: Submissions to medical and scientific journals are vetted by peer review, but peer review itself has been poorly studied until recently. One concern has been that manuscript reviews in which the reviewer is unblinded (e.g. knows author identity) may be biased, with an increased likelihood that the evaluation will not be strictly on scientific merits. OBJECTIVES: The purpose of this study was to compare the outcomes of blinded and unblinded reviews of manuscripts submitted to a single dermatology journal via a randomized multi-rater study. MATERIALS AND METHODS: Forty manuscripts submitted to the journal Dermatologic Surgery were assessed by four reviewers, two of whom were randomly selected to be blinded and two unblinded regarding the identities of the manuscripts' authors. The primary outcome measure was the initial score assigned to each manuscript by each reviewer characterized on an ordinal scale of 1-3, with 1 = accept; 2 = revise (i.e. minor or major revisions) and 3 = reject. Subgroup analysis compared the primary outcome measure across manuscripts from U.S. corresponding authors and foreign corresponding authors. The secondary outcome measure was word count of the narrative portion (i.e. comments to editor and comments to authors) of the reviewer forms. RESULTS: There was no significant difference between the scores given to manuscripts by unblinded reviewers and blinded reviewers, both for manuscripts from the U.S. and for foreign submissions. There was also no difference in word count between unblinded and blinded reviews. CONCLUSIONS: It seems, at least in the case of one dermatology journal, that blinding during peer review does not appear to affect the disposition of the manuscript. To the extent that review word count is a proxy for review quality, there appears to be no quality difference associated with blinding.

Melanoma in solid organ transplant recipients.

This manuscript outlines estimated risk and clinical course of pretransplant MM, donor-transmitted MM and de novo MM posttransplantation and includes an analysis of risk factors for metastasis, data from clinical studies and current and proposed management. MM in situ and thin melanoma (<1 mm) in the transplant population has similar recurrence and survival estimates to those in the general population. A minimum wait time of 2 years prior to transplantation is suggested for MM with a Breslow depth <1 mm and no clinical evidence of metastasis. More advanced MM may adopt a more aggressive course in transplant recipients. Sentinel lymph node biopsy may be of additional prognostic benefit. Revision of immunosuppression in the management of de novo melanoma in collaboration with the transplant team should be considered. Larger studies utilizing uniform staging criteria or at minimum Breslow depth, are required to assess true risk and outcome of MM in the immunosuppressed transplant population. Emphasis remains on patient education and regular screening to provide early detection of MM.

Homologous recombination and the repair of double-strand breaks during cotransformation of Dictyostelium discoideum.

We examined the ability of unlinked nonreplicating plasmid molecules to undergo homologous recombination during cotransformation of Dictyostelium amoebae. The transformation vector B10S confers resistance to the antibiotic G418 and was always presented to amoebae as a closed circle. Cotransforming DNA, containing a slime mold cDNA and sequences homologous to the primary vector, was presented either as a closed circle or as a linear molecule after digestion with restriction endonucleases which cut within one of three distinct regions of the plasmid. Remarkably, homologous recombination occurred in every clone examined. Moreover, the products of recombination were identical in all instances, irrespective of the presence or position of linearized ends. The ends of the linear templates were not recombinogenic. Repair of the introduced double-strand break occurred frequently during recombination. The repair could occur intermolecularly or, more likely, intramolecularly, i.e., by recircularization. Many of the recombination events were of a nonreciprocal nature. Despite the startlingly frequent level of homologous recombination, the use of cotransforming DNA which contains no homology to the selected vector established that such recombination was not required for cotransformation.

Effects of protein synthesis inhibition on the transcription and transcript stability of Dictyostelium prespore genes.

The in vivo accumulation of several prespore transcripts of Dictyostelium discoideum has previously been shown to depend upon concomitant protein synthesis (Ratner, D.I., Pentz, W.H. and Pelletier, D.A. (1989) Biochim. Biophys. Acta 1008, 71-78). Measurements of in vivo mRNA decay and nuclear run-on transcription assays have now been used to learn whether protein synthesis is required primarily for mRNA synthesis or transcript stability. The translational inhibitors cycloheximide and pactamycin stabilized existing prespore transcripts, despite their effect upon mRNA accumulation. Transcriptional assays, performed at intervals throughout the developmental cycle, demonstrated that temporal changes in the abundance of several cell-specific transcripts correlated closely with changes in their rates of synthesis. Finally, blocking protein synthesis strongly inhibited the transcription of the prespore genes examined. These results imply that one or more developmentally regulated, labile proteins are needed for the activation of prespore gene transcription.

Prespore gene expression in Dictyostelium requires concomitant protein synthesis.

It has been established previously that the maintenance of expression of prespore-specific genes of Dictyostelium discoideum is prevented by the translational inhibitor cycloheximide. The drug had no effect upon the level of transcripts of the other genes examined, prestalk-specific or cell type non-specific (Mehdy, M., Ratner, D. and Firtel, R., (1983) Cell 32, 763-771). We have now characterized the cellular specificity and temporal profiles of mRNA accumulation of additional Dictyostelium cDNA clones. Other inhibitors of in vivo protein synthesis have been examined, with emetine shown to be a particularly effective but reversible agent. Four structurally and mechanistically distinct translational inhibitors each prevented the reaccumulation of prespore transcripts in cyclic AMP-primed disaggregated amoebae. These results establish a role for protein synthesis in the transcription or transcript stability of prespore genes.

Angioplasty of complex lesions in ischemic rest angina: results of the Thrombolysis and Angioplasty in Unstable Angina (TAUSA) trial.

OBJECTIVES: This study sought to analyze the role of complex lesion morphology on the acute results of angioplasty. BACKGROUND: Acute complications of angioplasty are higher in unstable than in stable angina. The unstable culprit lesion is usually complex, indicative of plaque disruption and thrombus formation. Previous nonrandomized studies have shown that the presence of intracoronary thombus increases morbidity after coronary angioplasty. The role of complex morphology in coronary angioplasty outcome was studied in a prespecified subgroup analysis of a large multicenter coronary angioplasty trial. METHODS: The results of coronary angioplasty from the Thrombolysis and Angioplasty in Unstable Angina (TAUSA) trial were analyzed. This large trial randomized 469 patients in double-blinded manner to receive either intracoronary urokinase or placebo during coronary angioplasty of the culprit lesion in ischemic rest angina with or without recent infarction. The study presented here analyzes in detail the results of coronary angioplasty in complex versus simple lesions in the urokinase and placebo groups. Complex lesions were defined before angioplasty by a core laboratory as having one or more of the following: irregular borders, overhanging edges, ulcerations or intraluminal filling defects proximal or distal to the lesion. RESULTS: Of the 469 patients, 458 had identifiable culprit lesions, of which 245 were complex and 213 were simple. Complex lesions were associated with a higher abrupt closure rate than simple lesions (10.6% vs. 3.3%, respectively, p < 0.003). Patients with complex lesions also had higher recurrent in-hospital angina (p < 0.02) and emergent bypass surgery (p < 0.02). Further analysis of complex lesions revealed that abrupt closure was particularly high in the urokinase group (15.0% vs 5.9% for the placebo group, p < 0.03), and most abrupt closures were thrombotic. Composite clinical end points were also significantly higher with complex lesions and urokinase. In the placebo group, complex lesions had a higher abrupt closure rate as well as postcoronary angioplasty filling defects, but clinical end points were not significantly different. CONCLUSIONS: Complex lesions before coronary angioplasty increase acute complication rates after coronary angioplasty. Urokinase as administered in the TAUSA trial had significant adverse effects, especially in complex lesions. However, even in the placebo arm, complex lesions were associated with higher complication rates than simple lesions. Newer antithrombotic measures that particularly target the platelet may eventually decrease complication rates in these lesions.

Dynamic intracellular delivery of antibiotics via pH-responsive polymersomes.

Reversible addition-fragmentation chain transfer (RAFT) polymerization was employed to prepare a series of copolymers consisting of 2-hdroxyethyl methacrylate (HEMA) and poly(ethylene glycol) methyl ether methacrylate (FWavg ~ 950 Da) (O950) with variable comonomer compositions and molecular weights for use as polymeric scaffolds. Reactivity ratios for the monomer pair were determined to be 1.37 and 0.290 respectively. To these scaffolds trithiocarbonate-based RAFT chain transfer agents (CTAs) were grafted using carbodiimide chemistry. The resultant graft chain transfer agents (gCTA) were subsequently employed to polymerize dimethylaminoethyl methacrylate (DMAEMA) and (HPMA) between degrees of polymerization (DP) of 25 and 200. Kinetic analysis for the polymerization of DMAEMA targeting a DP of 100 from a 34 arm graft gCTA show linear Mn conversion and pseudo first order rate plots with narrow molecular weight distributions that move toward lower elution volumes with monomer conversion. D values for these polymerizations remain low at around 1.20 at monomer conversions as high as 70 %. pH-responsive endosomalytic brushes capable of spontaneously self-assembling into polymersomes were synthesized and a combination of dynamic light scattering (DLS), cryoTEM, and red blood cell hemolysis were employed to evaluate the aqueous solution properties of the polymeric brush as a function of pH. Successful encapsulation of ceftazidime and pH-dependent drug release properties were confirmed by HPLC. Intracellular antibiotic activity of the drug-loaded polymersomes was confirmed in a macrophage coculture model of infection with B. thailandensis and RAW 264.7 cells.

High-intensity double-pulse X-ray free-electron laser.

The X-ray free-electron laser has opened a new era for photon science, improving the X-ray brightness by ten orders of magnitude over previously available sources. Similar to an optical laser, the spectral and temporal structure of the radiation pulses can be tailored to the specific needs of many experiments by accurately manipulating the lasing medium, that is, the electron beam. Here we report the generation of mJ-level two-colour hard X-ray pulses of few femtoseconds duration with an XFEL driven by twin electron bunches at the Linac Coherent Light Source. This performance represents an improvement of over an order of magnitude in peak power over state-of-the-art two-colour XFELs. The unprecedented intensity and temporal coherence of this new two-colour X-ray free-electron laser enable an entirely new set of scientific applications, ranging from X-ray pump/X-ray probe experiments to the imaging of complex biological samples with multiple wavelength anomalous dispersion.

PTCH mutations in squamous cell carcinoma of the skin.

Ultraviolet light exposure is the major risk factor for the development of squamous cell carcinoma in Caucasians. Mutations in the tumor suppressor gene p53 have been identified in both squamous cell carcinomas and basal cell carcinomas. The human homolog of the Drosophila patched gene, has been shown to be mutated in sporadic basal cell carcinomas; however, mutations in the patched gene have not been found in squamous cell carcinoma. In this study, we screened a total of 20 squamous cell carcinoma samples for mutations in the patched gene. Using polymerase chain reaction-single strand conformation polymorphism as an initial screening method, we identified one non-sense mutation, two mis-sense mutations and three silent mutations in five squamous cell carcinoma samples. In one squamous cell carcinoma sample, we identified a tandem GG-->AA transitional change at nucleotide 3152 in exon 18 of the patched gene that resulted in a premature stop codon at codon 1051. The three squamous cell carcinoma samples containing non-sense and mis-sense mutations were isolated from individuals with histories of multiple basal cell carcinoma. Sequence analysis of the p53 gene in these five squamous cell carcinoma samples identified one CC-->TT and three C-->T ultraviolet-specific nucleotide changes. Our study provides evidence that the patched gene is mutated in squamous cell carcinoma from individuals with a history of multiple basal cell carcinoma. The identification of ultraviolet-specific nucleotide changes in both tumor suppressor genes supports the notion that ultraviolet exposure plays an important part in the development of squamous cell carcinoma.