Erratum: Using Diffuse Scattering to Observe X-Ray-Driven Nonthermal Melting [Phys. Rev. Lett. 126, 015703 (2021)].

This corrects the article DOI: 10.1103/PhysRevLett.126.015703.

Proton beam quality enhancement by spectral phase control of a PW-class laser system.

We report on experimental investigations of proton acceleration from solid foils irradiated with PW-class laser-pulses, where highest proton cut-off energies were achieved for temporal pulse parameters that varied significantly from those of an ideally Fourier transform limited (FTL) pulse. Controlled spectral phase modulation of the driver laser by means of an acousto-optic programmable dispersive filter enabled us to manipulate the temporal shape of the last picoseconds around the main pulse and to study the effect on proton acceleration from thin foil targets. The results show that applying positive third order dispersion values to short pulses is favourable for proton acceleration and can lead to maximum energies of 70 MeV in target normal direction at 18 J laser energy for thin plastic foils, significantly enhancing the maximum energy compared to ideally compressed FTL pulses. The paper further proves the robustness and applicability of this enhancement effect for the use of different target materials and thicknesses as well as laser energy and temporal intensity contrast settings. We demonstrate that application relevant proton beam quality was reliably achieved over many months of operation with appropriate control of spectral phase and temporal contrast conditions using a state-of-the-art high-repetition rate PW laser system.

Using Diffuse Scattering to Observe X-Ray-Driven Nonthermal Melting.

We present results from the SPring-8 Angstrom Compact free electron LAser facility, where we used a high intensity (∼10^{20} W/cm^{2}) x-ray pump x-ray probe scheme to observe changes in the ionic structure of silicon induced by x-ray heating of the electrons. By avoiding Laue spots in the scattering signal from a single crystalline sample, we observe a rapid rise in diffuse scattering and a transition to a disordered, liquidlike state with a structure significantly different from liquid silicon. The disordering occurs within 100 fs of irradiation, a timescale that agrees well with first principles simulations, and is faster than that predicted by purely inertial behavior, suggesting that both the phase change and disordered state reached are dominated by Coulomb forces. This method is capable of observing liquid scattering without masking signal from the ambient solid, allowing the liquid structure to be measured throughout and beyond the phase change.

Self-generated surface magnetic fields inhibit laser-driven sheath acceleration of high-energy protons.

High-intensity lasers interacting with solid foils produce copious numbers of relativistic electrons, which in turn create strong sheath electric fields around the target. The proton beams accelerated in such fields have remarkable properties, enabling ultrafast radiography of plasma phenomena or isochoric heating of dense materials. In view of longer-term multidisciplinary purposes (e.g., spallation neutron sources or cancer therapy), the current challenge is to achieve proton energies well in excess of 100 MeV, which is commonly thought to be possible by raising the on-target laser intensity. Here we present experimental and numerical results demonstrating that magnetostatic fields self-generated on the target surface may pose a fundamental limit to sheath-driven ion acceleration for high enough laser intensities. Those fields can be strong enough (~105 T at laser intensities ~1021 W cm-2) to magnetize the sheath electrons and deflect protons off the accelerating region, hence degrading the maximum energy the latter can acquire.

Scintillator-based transverse proton beam profiler for laser-plasma ion sources.

A high repetition rate scintillator-based transverse beam profile diagnostic for laser-plasma accelerated proton beams has been designed and commissioned. The proton beam profiler uses differential filtering to provide coarse energy resolution and a flexible design to allow optimisation for expected beam energy range and trade-off between spatial and energy resolution depending on the application. A plastic scintillator detector, imaged with a standard 12-bit scientific camera, allows data to be taken at a high repetition rate. An algorithm encompassing the scintillator non-linearity is described to estimate the proton spectrum at different spatial locations.

Ethical issues in decision-making for infants with disorders of sex development.

Medical decisions for infants and children should generally be based on the best interests of the child. When there is legitimate controversy over the child's best interests, the right of the child to an open future should generally determine the course of treatment. In the case of infants born with disorders of sex development (DSD), early cosmetic genitoplasty was long believed to be in the child's best interest and was therefore the standard of care. New data suggest that early genitoplasty may be more harmful than helpful, therefore the best interest standard is no longer determinative in such cases. Because children born with DSD have a right to an open future, and because the openness of their future is clearly enhanced by delaying cosmetic genitoplasty until they themselves can participate meaningfully in decision-making, early genitoplasty is ethically supportable only when medically indicated (e.g., when the child is unable to urinate without surgical intervention). Further research is needed to clarify the benefits and burdens of early and delayed genitoplasty. In parallel with further research, efforts should focus on educating society broadly to decrease stigmatization of persons with DSD.

Landscape of genetic lesions in 944 patients with myelodysplastic syndromes.

High-throughput DNA sequencing significantly contributed to diagnosis and prognostication in patients with myelodysplastic syndromes (MDS). We determined the biological and prognostic significance of genetic aberrations in MDS. In total, 944 patients with various MDS subtypes were screened for known/putative mutations/deletions in 104 genes using targeted deep sequencing and array-based genomic hybridization. In total, 845/944 patients (89.5%) harbored at least one mutation (median, 3 per patient; range, 0-12). Forty-seven genes were significantly mutated with TET2, SF3B1, ASXL1, SRSF2, DNMT3A, and RUNX1 mutated in >10% of cases. Many mutations were associated with higher risk groups and/or blast elevation. Survival was investigated in 875 patients. By univariate analysis, 25/48 genes (resulting from 47 genes tested significantly plus PRPF8) affected survival (P<0.05). The status of 14 genes combined with conventional factors revealed a novel prognostic model ('Model-1') separating patients into four risk groups ('low', 'intermediate', 'high', 'very high risk') with 3-year survival of 95.2, 69.3, 32.8, and 5.3% (P<0.001). Subsequently, a 'gene-only model' ('Model-2') was constructed based on 14 genes also yielding four significant risk groups (P<0.001). Both models were reproducible in the validation cohort (n=175 patients; P<0.001 each). Thus, large-scale genetic and molecular profiling of multiple target genes is invaluable for subclassification and prognostication in MDS patients.

Assessment of preoperative exercise capacity in hepatocellular carcinoma patients with chronic liver injury undergoing hepatectomy.

BACKGROUND: Cardiopulmonary exercise testing measures oxygen uptake at increasing levels of work and predicts cardiopulmonary performance under conditions of stress, such as after abdominal surgery. Dynamic assessment of preoperative exercise capacity may be a useful predictor of postoperative prognosis. This study examined the relationship between preoperative exercise capacity and event-free survival in hepatocellular carcinoma (HCC) patients with chronic liver injury who underwent hepatectomy. METHODS: Sixty-one HCC patients underwent preoperative cardiopulmonary exercise testing to determine their anaerobic threshold (AT). The AT was defined as the break point between carbon dioxide production and oxygen consumption per unit of time (VO2). Postoperative events including recurrence of HCC, death, liver failure, and complications of cirrhosis were recorded. Univariate and multivariate analyses were performed to evaluate associations between 35 clinical factors and outcomes, and identify independent prognostic indicators of event-free survival and maintenance of Child-Pugh class. RESULTS: Multivariate analyses identified preoperative branched-chain amino acid/tyrosine ratio (BTR) <5, alanine aminotransferase level ≥42 IU/l, and AT VO2 <11.5 ml/min/kg as independent prognostic indicators of event-free survival. AT VO2 <11.5 ml/min/kg and BTR <5 were identified as independent prognostic indicators of maintenance of Child-Pugh class. CONCLUSIONS: This study identified preoperative exercise capacity as an independent prognostic indicator of event-free survival and maintenance of Child-Pugh class in HCC patients with chronic liver injury undergoing hepatectomy.

Tunable radiation source by coupling laser-plasma-generated electrons to a periodic structure.

Near-infrared radiation around 1000 nm generated from the interaction of a high-density MeV electron beam, obtained by impinging an intense ultrashort laser pulse on a solid target, with a metal grating is observed experimentally. Theoretical modeling and particle-in-cell simulation suggest that the radiation is caused by the Smith-Purcell mechanism. The results here indicate that tunable terahertz radiation with tens GV/m field strength can be achieved by using appropriate grating parameters.

Fast focusing of short-pulse lasers by innovative plasma optics toward extreme intensity.

We developed a compact plasma-based focusing optic that, in one step, increases the peak intensity of ultrahigh-intensity lasers without modifying the laser system itself. By using a plasma-based focusing optic with extremely small f-number (f/0.4), we have experimentally demonstrated a fivefold reduction of the focal spot size (from 4.4 to 0.9 microm), thus producing an at least eightfold enhancement of the laser light intensity. This innovative plasma-based optic opens the way for the study of high-energy-density and high-field science at intensities greater than presently available.

Alterations in endogenous nitric oxide production after cardiopulmonary bypass in lambs with normal and increased pulmonary blood flow.

BACKGROUND: After cardiopulmonary bypass (CPB), altered vascular reactivity is a major source of complications, particularly for children with increased pulmonary blood flow. Although changes in agonist-induced NO activity are well described after CPB, potential changes in basal NO production and their role in post-CPB pulmonary hypertension remain unclear. By using aortopulmonary vascular graft placement in the fetal lamb (shunt lambs), we established a unique model of pulmonary hypertension that mimics congenital heart disease with increased pulmonary blood flow. The objective of the present study was to investigate potential alterations in endogenous NO production after CPB in lambs with normal and increased pulmonary blood flow. METHODS AND RESULTS: Vascular pressures and blood flows were monitored in 1-month-old lambs (n=7) with increased pulmonary blood flow and 6 age-matched control lambs. After shunt closure, hypothermic CPB (25 degrees C) was performed for 2 hours. The hemodynamic variables were monitored for 4 hours after CPB. Before, during, and after CPB, peripheral lung biopsies were performed to determine tissue NO, nitrite, nitrate, and cGMP concentrations; total NO synthase (NOS) activity; and endothelial NOS protein levels. Hypothermic CPB increased both mean pulmonary arterial pressure and left pulmonary vascular resistance (P:<0.05). The increase in pulmonary arterial pressure induced in shunt lambs was greater than that induced in control lambs (P:<0.05). Four hours after CPB, tissue concentrations of NO, nitrite, nitrate, and cGMP were decreased to approximately 70% of pre-CPB levels in both control and shunt lambs (P:<0.05). Total NOS activity and endothelial NOS protein levels were unchanged. CONCLUSIONS: Modest decreases in basal NO production, the inability to increase NO production, or both may play a role in the altered pulmonary vascular reactivity after CPB. The decrease in NO is independent of gene expression. However, other mechanisms for this decrease, such as substrate or cofactor availability, warrant further study.

Expression vector with DNA of bovine papilloma virus 1 for keratinocyte gene therapy.

Although there are several methods for introducing the genes to keratinocytes in vivo, expression of transgene does not last long enough for effective keratinocyte gene therapy. In this study, we added bovine papilloma virus 1 (BPV) DNA into expression vectors with the lacZ gene driven by metallothionein and keratin 10 promoters, and we transferred them into keratinocytes in vivo using the naked DNA method, and measured beta-gal activity in keratinocytes. The results showed that beta-galactosidase activity of vectors with the BPV DNA was clearly higher than that without the DNA. Moreover, time-course experiment disclosed that the activity of the BPV vector declined at a lower rate than that of the control vector, suggesting this fragment prolonged transgene expression. These results should prove useful for understanding gene regulation in keratinocytes in vivo and for developing potential expression vectors for keratinocyte gene therapy.

In vivo gene introduction into keratinocytes using jet injection.

Successful keratinocyte gene therapy requires the development of efficient methods of gene transfer to keratinocytes. Jet injection of a solution containing DNA can be used to transfer genes to several tissues in vivo. In this article, we tried to introduce DNA into rat and human keratinocytes using this method. First, we fired a beta-gal expression vector into rat skin at several distances using a jet injector and examined beta-gal activity in the epidermal keratinocytes. The highest activity in keratinocytes was found when the plasmid was fired at 10 cm from the skin surface; the activity lessened as the firing distance became shorter than 10 cm. Next, we transplanted human skin on to a nude rat, fired the vector into the human skin from a distance of 10 cm and examined the beta-gal activity. We also injected the same amount of plasmid with a needle to compare jet with needle injections. The results showed that jet injection of the naked DNA could introduce and express DNA in human keratinocytes in vivo and that jet injection exhibited much higher activity than needle injection. Jet injection of the naked DNA will provide a method for keratinocyte gene therapy in the future.

Diagnostic dilemma of "sporadic" cases of dystrophic epidermolysis bullosa: a new dominant or mitis recessive mutation?

Dystrophic forms of epidermolysis bullosa (DEB), characterized by mutations in the type VII collagen gene (COL7A1), are inherited either in an autosomal dominant or autosomal recessive fashion, and sporadic, de novo cases have also been reported. Clinically, the dominant forms (DDEB) can be indistinguishable from the mild, mitis forms of recessively inherited DEB (M-RDEB). This situation poses a dilemma in case of families with 1 mildly affected individual and clinically normal parents: Is it a new dominant or mitis recessive DEB? In this study we review 2 cases with mild DEB, the parents being clinically normal. One of the cases was shown to be a compound heterozygote for 2 silent missense mutations (R2063W/G2366S), thus being diagnosed as M-RDEB. The second case had a single glycine substitution mutation (G2079E) in COL7A1 and had therefore DDEB. These findings have implications for the genetic counseling of these families concerning the risk of recurrence of the disease in subsequent pregnancies in the present and future generations.