Blastic Plasmacytoid Dendritic Cell Neoplasm: A Single-Center Experience. Clinical Characterization, Mutational Landscape, and Clinical Outcome of Patients Undergoing Hematopoietic Stem Cell Transplantation Intensive Therapy.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive hematodermic neoplasm usually involving the skin. In this retrospective case series, 10 cases of BPDCN were identified, 90% of which had skin involvement and exhibited predominantly violaceous nodules and/or bruise-like plaques. Skin lesions showed diffuse or nodular dermal-based infiltrates of intermediate sized blasts with a grenz zone. Tumor immunophenotyping was CD4(+), CD56(+), CD123(+) and CD303(+). The most frequently mutated genes according to targeted next-generation sequencing were TET2 (3/7) and NRAS (2/7). Multiagent chemotherapy (CT) was administered as first-line therapy, and a total of 5 patients underwent allogenic hematopoietic stem cell transplantation (allo-HSCT). Better outcomes were observed in younger patients and those treated with acute lymphoblastic leukemia (ALL)-like CT followed by allo-HSCT. This study shows the clinical range of cutaneous lesions of BPDCN. Despite the absence of a gold standard therapy, patients treated with myeloablative intensive regimens and allo-HSCT seems to have a more favorable prognosis.

Range verification in heavy-ion therapy using a hadron tumour marker.

Objective.A new method to estimate the range of an ion beam in a patient during heavy-ion therapy was investigated, which was previously verified for application in proton therapy.Approach.The method consists of placing a hadron tumour marker (HTM) close to the tumour. As the treatment beam impinges on the HTM, the marker undergoes nuclear reactions. When the HTM material is carefully chosen, the activation results in the emission of several delayed, characteristicγrays, whose intensities are correlated with the remaining range inside the patient. When not just one but two reaction channels are investigated, the ratio between these twoγray emissions can be measured, and the ratio is independent of any beam delivery uncertainties.Main results.A proof-of-principle experiment with an16O ion beam and Ag foils as HTM was successfully executed. The107Ag(16O,x)112Sb and the107Ag(16O,x)114Sb reaction channels were identified as suitable for the HTM technique. When only oneγ-ray emission is measured, the resulting range-uncertainty estimation is at the 0.5 mm scale. When both channels are considered, a theoretical limit on the range uncertainty of a clinical fiducal marker was found to be ±290µm.Significance.Range uncertainty of a heavy-ion beam limits the prescribed treatment plan for cancer patients, especially the direction of the ion beam in relation to any organ at risk. An easy to implement range-verification technique which can be utilized during clinical treatment would allow treatment plans to take full advantage of the sharp fall-off of the Bragg peak without the risk of depositing excessive dose into healthy tissue.

[Examinations of cattle births with a special focus on Coxiella burnetii]. / Geburten an der Wiederkäuerklinik mit Fokus auf die Ausscheidung von Coxiella burnetii.

INTRODUCTION: Cattle births can carry the risk of transmissible and zoonotic diseases. The focus of the present study was the excretion of Coxiella (C.) burnetii during cattle births. Small ruminants are considered as the main reservoir of C. burnetii. Cattle are often subclinical carriers and their role as potential reservoir has not been fully elucidated until now, although the excretion of Coxiella has been demonstrated during cattle birth. The study recorded all births, caesarean sections and one abortion in 40 cattle at the ruminant clinic of the Vetsuisse Faculty in Bern in the study period from March 2019 to March 2020. A placenta -, milk - and fecal sample was examined for antigen diagnostics using polymerase chain reaction (PCR). In addition, a serum sample was analyzed to detect C. burnetii-specific antibodies. Antigen and/or antibodies (placenta, n=8/9; milk, n=2/9; faeces, n=1/9; serology n= 3/9) were detected in 22,5 % of the cows (n=9/40) without the presence of specific clinical symptoms. It is essential to sensitize contact persons to this zoonosis, since Coxiella can trigger Q-fever in humans.

INTRODUCTION: Les naissances chez les bovins peuvent comporter un risque de maladies transmissibles et zoonotiques. La présente étude se concentre sur l'excrétion de Coxiella (C.) burnetii lors des mises-bas de bovins. Les petits ruminants sont considérés comme le principal réservoir de C. burnetii, mais les bovins sont souvent des porteurs subcliniques et leur rôle de réservoir potentiel n'a pas été complètement élucidé jusqu'à présent, bien que l'excrétion de Coxiella ait été démontrée lors de la mise-bas. L'étude a recensé toutes les naissances, les césariennes et un avortement chez 40 bovins à la Clinique des ruminants de la Faculté Vetsuisse de Berne durant la période allant de mars 2019 à mars 2020. Un échantillon de placenta, de lait et de matières fécales a été examiné pour le diagnostic des antigènes par réaction en chaîne par polymérase (PCR). En outre, un échantillon de sérum a été analysé pour détecter les anticorps spécifiques de C. burnetii. L'antigène et/ou les anticorps (placenta, n=8/9 ; lait, n=2/9 ; fèces, n=1/9 ; sérologie n=3/9) ont été détectés chez 22,5 % des vaches (n=9/40) sans présence de symptômes cliniques spécifiques. Il est essentiel de sensibiliser les personnes de contact à cette zoonose, car Coxiella peut déclencher la fièvre Q chez l'homme.

Investigating charge-up and fragmentation dynamics of oxygen molecules after interaction with strong X-ray free-electron laser pulses.

During the last decade, X-ray free-electron lasers (XFELs) have enabled the study of light-matter interaction under extreme conditions. Atoms which are subject to XFEL radiation are charged by a complex interplay of (several subsequent) photoionization events and electronic decay processes within a few femtoseconds. The interaction with molecules is even more intriguing, since intricate nuclear dynamics occur as the molecules start to dissociate during the charge-up process. Here, we demonstrate that by analyzing photoelectron angular emission distributions and kinetic energy release of charge states of ionic molecular fragments, we can obtain a detailed understanding of the charge-up and fragmentation dynamics. Our novel approach allows for gathering such information without the need of complex ab initio modeling. As an example, we provide a detailed view on the processes happening on a femtosecond time scale in oxygen molecules exposed to intense XFEL pulses.

Beam particle identification and tagging of incompletely stripped heavy beams with HEIST.

A challenge preventing successful inverse kinematics measurements with heavy nuclei that are not fully stripped is identifying and tagging the beam particles. For this purpose, the HEavy ISotope Tagger (HEIST) has been developed. HEIST utilizes two micro-channel plate timing detectors to measure the time-of-flight, a multi-sampling ion chamber to measure energy loss, and a high-purity germanium detector to identify isomer decays and calibrate the isotope identification system. HEIST has successfully identified 198Pb and other nearby nuclei at energies of about 75 MeV/A. In the experiment discussed, a typical cut containing 89% of all 198Pb80+ in the beam had a purity of 86%. We examine the issues of charge state contamination. The observed charge state populations of these ions are presented and, using an adjusted beam energy, are well described by the charge state model GLOBAL.

Foam-lined hohlraum, inertial confinement fusion experiments on the National Ignition Facility.

Experiments on the National Ignition Facility (NIF) to study hohlraums lined with a 20-mg/cc 400-µm-thick Ta_{2}O_{5} aerogel at full scale (hohlraum diameter = 6.72 mm) are reported. Driven with a 1.6-MJ, 450-TW laser pulse, the performance of the foam liner is diagnosed using implosion hot-spot symmetry measurements of the high-density carbon (HDC) capsule and measurement of inner beam propagation through a thin-wall 8-µm Au window in the hohlraum. Results show an improved capsule performance due to laser energy deposition further inside the hohlraum, leading to a modest increase in x-ray drive and reduced preheat due to changes in the x-ray spectrum when the foam liner is included. In addition, the outer cone bubble uniformity is improved, but the predicted improvement in inner beam propagation to improve symmetry control is not realized for this foam thickness and density.

Photon-recoil imaging: Expanding the view of nonlinear x-ray physics.

Addressing the ultrafast coherent evolution of electronic wave functions has long been a goal of nonlinear x-ray physics. A first step toward this goal is the investigation of stimulated x-ray Raman scattering (SXRS) using intense pulses from an x-ray free-electron laser. Earlier SXRS experiments relied on signal amplification during pulse propagation through dense resonant media. By contrast, our method reveals the fundamental process in which photons from the primary radiation source directly interact with a single atom. We introduce an experimental protocol in which scattered neutral atoms rather than scattered photons are detected. We present SXRS measurements at the neon K edge and a quantitative theoretical analysis. The method should become a powerful tool in the exploration of nonlinear x-ray physics.

Long-term outcomes of rituximab therapy in pemphigus.

BACKGROUND: Rituximab induces a rapid remission in most patients with pemphigus. OBJECTIVE: Our aim was to assess the long-term efficacy of rituximab in this disease. METHOD: We conducted a retrospective study of 59 patients with pemphigus treated with rituximab and observed over a median period of 104 months. RESULTS: The rate of complete remission off therapy (CRoff) after the first rituximab cycle was 39%, increasing to 61% with additional rituximab courses. Long-term CRoff was achieved in 27% of patients. The recurrence rate after the first rituximab cycle was 63%, decreasing to approximately 40% with subsequent rituximab cycles. Median time to relapse after the first and subsequent rituximab cycles was 25 months. Renewed rituximab therapy reinduced complete remission in 94% of cases. Baseline anti-desmoglein antibody levels of ≤250 U/mL were significantly associated with the outcome of CRoff. In paired serum samples obtained before the first and six months after the last rituximab therapy, significant reductions of desmoglein-specific autoantibodies were observed. Patients relapsing after a complete remission induced by the first rituximab cycle were more likely to achieve CRoff than patients relapsing after a less favourable outcome and non-responders. There was no significant difference in age, sex, pemphigus subtype, rituximab dosing and disease duration between patients achieving CRoff and those not meeting this end point. CONCLUSIONS: Lower desmoglein-specific antibody levels at baseline were predictive of CRoff. In patients receiving multiple rituximab cycles, complete remission after the first cycle was associated with a favourable long-term outcome. Repeated rituximab courses were highly effective for relapsed disease and improved the overall outcome.

Results of R-ESHAP as salvage therapy in refractory/relapsed follicular lymphoma: a real-world experience on behalf of GELCAB group.

There is no standard treatment for relapsed follicular lymphoma (FL). Although platinum-based combinations are one of the most used treatments, few data have been reported in this setting. Our aim was to analyse R-ESHAP efficacy in relapsed FL patients. We retrospectively analysed 80 FL patients treated with R-ESHAP in the first or successive relapses. Responding patients received a stem cell transplantation following R-ESHAP. Seventeen histologically transformed patients were included. Median age was 50 years. At R-ESHAP initiation, 85% of the patients were in an advanced stage, 28% had a bulky disease and 40% had increased LDH. There were no statistically significant differences between POD24 and non-POD24 patients in terms of response to R-ESHAP (ORR 72% vs. 93%, p = 0.109). When analyzing R-ESHAP efficacy according to the response to the immediately previous line, patients achieving CR or PR had better CR rates to R-ESHAP than those who did not respond (CR of 57% vs. 15%, respectively, p = 0.009), as well as differences in OS (7.2 vs. 1.4 years, p < 0.0001) and in PFS (2.1 vs. 0.3 years, p < 0.0001). R-ESHAP is an effective treatment in relapsed FL patients who respond to the previous line and has to be considered as an adequate alternative for some patients.

Quantitative evaluation of the progressive wear of powered interproximal reduction systems after repeated use : An in vitro study.

PURPOSE: To evaluate the residual surface roughness of 5 common diamond-coated interproximal reduction (IPR) systems after consecutive in vitro applications in relation to system, diamond grain size, and instrument thickness. METHODS: IPR was performed on 80 extracted human incisors using motor-driven strips and discs under predefined conditions. The IPR auxiliaries were applied at 5 consecutive sessions of 20 s on intact interproximal surfaces, and the surface profile (Ra, Rz, Rmax) was analyzed at baseline and after each session with an optical profilometer. RESULTS: No overall significant difference in the roughness values was found between systems (P = 0.07 for Ra, P = 0.33 for Rz, and P = 0.48 for Rmax). There was a significant average decrease of Ra, Rz, and Rmax for all systems for every unit increase in time by -0.171 µm (P < 0.001), -3.297 (P ≤ 0.001), and -2.788 µm (P = 0.001), respectively. Ra, Rz, and Rmax values increased significantly, i.e., by 0.194 µm (P = 0.003), 5.890 µm (P = 0.001), and 5.319 µm (P = 0.010) as instrument thickness increased by one unit. No significant reductions in Ra, Rz, and Rmax were observed across grain sizes (-0.008 µm [P > 0.05], -0.244 µm [P > 0.05], and -0.179 µm [P > 0.05], respectively). There was no evidence of interaction between system and time as the P values for Ra, Rz, and Rmax were 0.88, 0.51, and 0.70, respectively. CONCLUSIONS: All IPR materials presented significant gradual decrease of surface roughness after repeated applications. There were no significant roughness changes among auxiliaries of different grain sizes. Thinner auxiliaries showed significantly more roughness reduction, possibly requiring more frequent replacement than thick auxiliaries in clinical practice.

[The pathologist Friedrich Feyrter in National Socialism]. / Der Pathologe Friedrich Feyrter im Nationalsozialismus.

BACKGROUND: Up until now, very little has been reported about the important pathologist Friedrich Feyrter in the time of National Socialism. OBJECTIVES: What was Feyrter's attitude towards National Socialism? METHODS: Bibliographic and previously unevaluated archival sources were subjected to a historical-critical examination. RESULTS: Feyrter was a member of the Nazi Party. In 1938 and 1950 he gave contradictory information concerning the year he joined the party. CONCLUSIONS: At the very least, he was a political opportunist.

Constraining the Neutron Star Compactness: Extraction of the

The ^{23}Al(p,γ)^{24}Si reaction is among the most important reactions driving the energy generation in type-I x-ray bursts. However, the present reaction-rate uncertainty limits constraints on neutron star properties that can be achieved with burst model-observation comparisons. Here, we present a novel technique for constraining this important reaction by combining the GRETINA array with the neutron detector LENDA coupled to the S800 spectrograph at the National Superconducting Cyclotron Laboratory. The ^{23}Al(d,n) reaction was used to populate the astrophysically important states in ^{24}Si. This enables a measurement in complete kinematics for extracting all relevant inputs necessary to calculate the reaction rate. For the first time, a predicted close-lying doublet of a 2_{2}^{+} and (4_{1}^{+},0_{2}^{+}) state in ^{24}Si was disentangled, finally resolving conflicting results from two previous measurements. Moreover, it was possible to extract spectroscopic factors using GRETINA and LENDA simultaneously. This new technique may be used to constrain other important reaction rates for various astrophysical scenarios.

The use of fluoride for the prevention of dental erosion and erosive tooth wear in children and adolescents.

BACKGROUND: Erosive tooth wear (ETW) has gained increasing clinical relevance. It is estimated that worldwide 30-50% of deciduous and 20-45% of permanent teeth are affected. One of the most important nutritional factors causing ETW is the overconsumption of soft drinks, but also patient-related factors like reflux or eating disorders can lead to erosive lesions. Whether acids lead to erosive demineralisation depends on their degree of saturation with respect to tooth mineral at their actual pH. REVIEW: Fluoride compounds like sodium or amine fluoride seem to be of limited efficacy against erosion, the main reason for this is the missing biofilm in the erosive process as well as the lower pH of the acids compared to bacterial acids. This means that to achieve some kind of preventive effect it would be necessary to use products with higher fluoride concentration, which is not an appropriate option for small children, and/or to increase the frequency of application. In addition, the fluoride compound plays a role as promising effects were found when fluoride is combined with titanium or stannous ions. TiF4 can cause acid-resistant surface coatings and when Sn2+/F- formulations are applied, Sn is not only found on the surface but is also incorporated into enamel and dentine. Both effects make the tooth surface more resistant against acid demineralisation. Different fluoride-containing vehicles have been tested to prevent erosion/ETW, such as toothpastes, rinses, gels and varnishes. Toothpastes offer some degree of protection, especially Sn2+-containing formulations, but effects of the active ingredients are sometimes counteracted by the presence of abrasives. CONCLUSION: Detecting associated factors and influencing them is the main instrument in arresting erosive tooth wear. Additionally, patients at risk for dental erosion should always use an additional fluoride source preferably containing Sn2+.

Control of H_{2} Dissociative Ionization in the Nonlinear Regime Using Vacuum Ultraviolet Free-Electron Laser Pulses.

The role of the nuclear degrees of freedom in nonlinear two-photon single ionization of H_{2} molecules interacting with short and intense vacuum ultraviolet pulses is investigated, both experimentally and theoretically, by selecting single resonant vibronic intermediate neutral states. This high selectivity relies on the narrow bandwidth and tunability of the pulses generated at the FERMI free-electron laser. A sustained enhancement of dissociative ionization, which even exceeds nondissociative ionization, is observed and controlled as one selects progressively higher vibronic states. With the help of ab initio calculations for increasing pulse durations, the photoelectron and ion energy spectra obtained with velocity map imaging allow us to identify new photoionization pathways. With pulses of the order of 100 fs, the experiment probes a timescale that lies between that of ultrafast dynamical processes and that of steady state excitations.

An electron beam ion trap and source for re-acceleration of rare-isotope ion beams at TRIUMF.

Electron beam driven ionization can produce highly charged ions (HCIs) in a few well-defined charge states. Ideal conditions for this are maximally focused electron beams and an extremely clean vacuum environment. A cryogenic electron beam ion trap fulfills these prerequisites and delivers very pure HCI beams. The Canadian rare isotope facility with electron beam ion source-electron beam ion sources developed at the Max-Planck-Institut für Kernphysik (MPIK) reaches already for a 5 keV electron beam and a current of 1 A with a density in excess of 5000 A/cm2 by means of a 6 T axial magnetic field. Within the trap, the beam quickly generates a dense HCI population, tightly confined by a space-charge potential of the order of 1 keV times the ionic charge state. Emitting HCI bunches of ≈107 ions at up to 100 Hz repetition rate, the device will charge-breed rare-isotope beams with the mass-over-charge ratio required for re-acceleration at the Advanced Rare IsotopE Laboratory (ARIEL) facility at TRIUMF. We present here its design and results from commissioning runs at MPIK, including X-ray diagnostics of the electron beam and charge-breeding process, as well as ion injection and HCI-extraction measurements.

Clinical impact of the subclonal architecture and mutational complexity in chronic lymphocytic leukemia.

Genome studies of chronic lymphocytic leukemia (CLL) have revealed the remarkable subclonal heterogeneity of the tumors, but the clinical implications of this phenomenon are not well known. We assessed the mutational status of 28 CLL driver genes by deep-targeted next-generation sequencing and copy number alterations (CNA) in 406 previously untreated patients and 48 sequential samples. We detected small subclonal mutations (0.6-25% of cells) in nearly all genes (26/28), and they were the sole alteration in 22% of the mutated cases. CNA tended to be acquired early in the evolution of the disease and remained stable, whereas the mutational heterogeneity increased in a subset of tumors. The prognostic impact of different genes was related to the size of the mutated clone. Combining mutations and CNA, we observed that the accumulation of driver alterations (mutational complexity) gradually shortened the time to first treatment independently of the clonal architecture, IGHV status and Binet stage. Conversely, the overall survival was associated with the increasing subclonal diversity of the tumors but it was related to the age of patients, IGHV and TP53 status of the tumors. In conclusion, our study reveals that both the mutational complexity and subclonal diversity influence the evolution of CLL.

The effect of different salivary calcium concentrations on the erosion protection conferred by the salivary pellicle.

Different proportions of mineral ions in saliva can influence the protective effect the salivary pellicle provides against dental erosion. To investigate the effect of different calcium concentrations in human saliva on the protection against enamel erosion, enamel specimens were divided into 8 treatment groups: humid chamber (Ctrl); whole mouth stimulated human saliva (HS); artificial saliva containing different calcium concentrations (ASlow, ASmedium, AShigh); and dialysed human saliva containing different calcium concentrations (DSlow, DSmedium, DShigh). The specimens underwent 4 cycles of incubation in the treatment group followed by an erosive challenge. Surface hardness and calcium release were measured during the cycling process. All DS groups exhibited significantly higher enamel surface softening than HS and the corresponding AS groups. Among the DS groups, the surface softening was significantly higher in DSlow than in DShigh. No significant differences were found within the AS or DS groups regarding calcium release. The results of this study indicated that erosion protection conferred by saliva depends on an interplay between salivary proteins and ions. While both proteins and ions have a positive effect on their own, the combination of the two can lead to different degrees of protection or even negative effects, depending on the relative concentrations.

Erosive effect of different dietary substances on deciduous and permanent teeth.

OBJECTIVES: We investigated the effect of different dietary substances on deciduous and permanent enamel. MATERIALS AND METHODS: Enamel specimens were prepared from human teeth (n = 108 deciduous molars and n = 108 permanent premolars). We measured the chemical parameters (pH, titratable acidity, viscosity, calcium, phosphate, fluoride concentration and degree of saturation) of nine dietary substances. The teeth were immersed in the respective substance (2 × 2 min; 30 °C; shaking), and we measured the baseline surface hardness (SH) in Vickers hardness numbers (VHN), and the changes in SH after 2 min (ΔSH2-0) and the 4 min (ΔSH4-0) immersion. We analysed the differences between deciduous and permanent teeth using the Wilcoxon test and correlated ΔSH to the different chemical parameters. RESULTS: Deciduous teeth were significantly softer (549.53 ± 59.41 VHN) than permanent teeth (590.15 ± 55.31 VHN; p < 0.001) at baseline, but they were not more vulnerable to erosive demineralization. Only orange juice, which presented milder erosive potential, caused significantly more demineralisation in deciduous teeth at ΔSH4-0. Practically all chemical parameters significantly correlated with ΔSH (p < 0.05). Substances with lower pH, higher titratable acidity, lower Ca, higher Pi and lower F concentrations, higher viscosity and more undersaturated solutions presented more erosive demineralisation. CONCLUSION: Different parameters in dietary substances affect erosive demineralisation in deciduous and permanent teeth, but we generally observed no differences in susceptibility to erosion between both types of teeth; only orange juice (less severe acid conditions) caused perceptible differences. CLINICAL RELEVANCE: We observe that permanent teeth are harder than deciduous teeth, but most substances cause no perceptible difference in erosive demineralisation in both types of teeth.

Erosion protection conferred by whole human saliva, dialysed saliva, and artificial saliva.

During dental erosion, tooth minerals are dissolved, leading to a softening of the surface and consequently to irreversible surface loss. Components from human saliva form a pellicle on the tooth surface, providing some protection against erosion. To assess the effect of different components and compositions of saliva on the protective potential of the pellicle against enamel erosion, we prepared four different kinds of saliva: human whole stimulated saliva (HS), artificial saliva containing only ions (AS), human saliva dialysed against artificial saliva, containing salivary proteins and ions (HS/AS), and human saliva dialysed against deionised water, containing only salivary proteins but no ions (HS/DW). Enamel specimens underwent four cycles of immersion in either HS, AS, HS/AS, HS/DW, or a humid chamber (Ctrl), followed by erosion with citric acid. During the cycling process, the surface hardness and the calcium released from the surface of the specimens were measured. The different kinds of saliva provided different levels of protection, HS/DW exhibiting significantly better protection than all the other groups (p < 0.0001). Different components of saliva, therefore, have different effects on the protective properties of the pellicle and the right proportions of these components in saliva are critical for the ability to form a protective pellicle.