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Laser plasma accelerators (LPAs) enable the generation of intense and short proton bunches on a micrometre scale, thus offering new experimental capabilities to research fields such as ultra-high dose rate radiobiology or material analysis. Being spectrally broadband, laser-accelerated proton bunches allow for tailored volumetric dose deposition in a sample via single bunches to excite or probe specific sample properties. The rising number of such experiments indicates a need for diagnostics providing spatially resolved characterization of dose distributions with volumes of approximately 1 cm ${}^3$ for single proton bunches to allow for fast online feedback. Here we present the scintillator-based miniSCIDOM detector for online single-bunch tomographic reconstruction of dose distributions in volumes of up to approximately 1 cm ${}^3$ . The detector achieves a spatial resolution below 500 $\unicode{x3bc}$ m and a sensitivity of 100 mGy. The detector performance is tested at a proton therapy cyclotron and an LPA proton source. The experiments’ primary focus is the characterization of the scintillator’s ionization quenching behaviour.

BackgroundRare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.MethodsWe did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.FindingsA locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.InterpretationThis is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.FundingUK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.

Abstract Right heart (RH) structure and function are major determinants of symptoms and prognosis in pulmonary arterial hypertension (PAH). RH imaging provides detailed information, but evidence and guidelines on the use of RH imaging in treatment decisions are limited. We conducted a Delphi study to gather expert opinion on the role of RH imaging in decision‐making for treatment escalation in PAH. A panel of 17 physicians with expertise in PAH and RH imaging used three surveys in a modified Delphi process to reach consensus on the role of RH imaging in PAH. Survey 1 used open‐ended questions to gather information. Survey 2 contained Likert scale and other questions intended to identify consensus on topics identified in Survey 1. Survey 3 contained Likert scale questions derived from Survey 2 and summary information on the results of Survey 2. The Delphi panel reached consensus that RH imaging is likely to improve the current risk stratification algorithms and help differentiate risk levels in patients at intermediate risk. Tricuspid annular plane systolic excursion, right ventricular fractional area change, right atrial area, tricuspid regurgitation, inferior venae cavae diameter, and pericardial effusion should be part of routine echocardiography in PAH. Cardiac magnetic resonance imaging is valuable but limited by cost and access. A pattern of abnormal RH imaging results should prompt consideration of hemodynamic evaluation and possible treatment escalation. RH imaging is an important tool for decisions about treatment escalation in PAH, but systematically collected evidence is needed to clarify its role.

With approximately 220,000 newly diagnosed cases per year, ovarian cancer is among the most frequently occurring cancers among women and the second leading cause of death from gynecological malignancies worldwide. About 70% of these cancers are diagnosed in advanced stages (FIGO IIB–IV), with a 5-year survival rate of 20–30%. Due to the poor prognosis of this disease, research has focused on its pathogenesis and the identification of prognostic factors. One possible approach for the identification of biological markers is the identification of tumor entity-specific genetic “driver mutations”. One such mutation is 3q26 amplification in the tumor driver SEC62, which has been identified as relevant to the pathogenesis of ovarian cancer. This study was conducted to investigate the role of SEC62 in ovarian malignancies. Patients with ovarian neoplasias (borderline tumors of the ovary and ovarian cancer) who were treated between January 2007 and April 2019 at the Department of Gynecology and Obstetrics, Saarland University Hospital, were included in this retrospective study. SEC62 expression in tumor tissue samples taken during clinical treatment was assessed immunohistochemically, with the calculation of immunoreactivity scores according to Remmele and Stegner, Pathologe, 1987, 8, 138–140. Correlations of SEC62 expression with the TNM stage, histological subtype, tumor entity, and oncological outcomes (progression-free and overall survival) were examined. The sample comprised 167 patients (123 with ovarian cancer and 44 with borderline tumors of the ovary) with a median age of 60 (range, 15–87) years. At the time of diagnosis, 77 (46%) cases were FIGO stage III. All tissue slides showed SEC62 overexpression in tumor cells and no SEC62 expression in other cells. Median immunoreactivity scores were 8 (range, 2–12) for ovarian cancer and 9 (range, 4–12) for borderline tumors of the ovary. Patients with borderline tumors of the ovary as well as patients with ovarian cancer and an immunoreactive score (IRS) ≤ 9 showed an improved overall survival compared to those presenting with an IRS score >9 (p = 0.03). SEC62 seems to be a prognostic biomarker for the overall survival of patients with ovarian malignancies.

Abstract Aim Human Immunodeficiency Virus (HIV) patients commonly experience dyspnea for which an immediate cause may not be always apparent. In this prospective cohort study of HIV patients with exercise limitation, we use cardiopulmonary exercise testing (CPET) coupled with exercise cardiovascular magnetic resonance (CMR) to elucidate etiologies of dyspnea. Methods and results Thirty-four HIV patients on antiretroviral therapy with dyspnea and exercise limitation (49.7 years, 65% male, mean absolute CD4 count 700) underwent comprehensive evaluation with combined rest and maximal exercise treadmill CMR and CPET. The overall mean oxygen consumption (VO2) peak was reduced at 23.2 ± 6.9 ml/kg/min with 20 patients (58.8% of overall cohort) achieving a respiratory exchange ratio > 1. The ventilatory efficiency (VE)/VCO2 slope was elevated at 36 ± 7.92, while ventilatory reserve (VE: maximal voluntary ventilation (MVV)) was within normal limits. The mean absolute right ventricular (RV) and left ventricular (LV) contractile reserves were preserved at 9.0% ± 11.2 and 9.4% ± 9.4, respectively. The average resting and post-exercise mean average pulmonary artery velocities were 12.2 ± 3.9 cm/s and 18.9 ± 8.3 respectively, which suggested lack of exercise induced pulmonary artery hypertension (PAH). LV but not RV delayed enhancement were identified in five patients. Correlation analysis found no relationship between peak VO2 measures of contractile RV or LV reserve, but LV and RV stroke volume correlated with PET CO2 (p = 0.02, p = 0.03). Conclusion Well treated patients with HIV appear to have conserved RV and LV function, contractile reserve and no evidence of exercise induced PAH. However, we found evidence of impaired ventilation suggesting a non-cardiopulmonary etiology for dyspnea.

Laser-plasma accelerators (LPAs) can deliver pico- to nanosecond long proton bunches with ≳100 nC of charge dispersed over a broad energy spectrum. Increasing the repetition rates of today's LPAs is a necessity for their practical application. This, however, creates a need for real-time proton bunch diagnostics. Scintillating screens are one detector solution commonly applied in the field of electron LPAs for spatially resolved particle and radiation detection. Yet their establishment for LPA proton detection is only slowly taking off, also due to the lack of available calibrations. In this paper, we present an absolute proton number calibration for the scintillating screen type DRZ High (Mitsubishi Chemical Corporation, Düsseldorf, Germany), one of the most sensitive screens according to calibrations for relativistic electrons and x rays. The presented absolute light yield calibration shows an uncertainty of the proton number of 10% and can seamlessly be applied at other LPA facilities. For proton irradiation of the DRZ High screen, we find an increase in light yield of > 60% compared to reference calibration data for relativistic electrons. Moreover, we investigate the scintillating screen light yield dependence on proton energy since many types of scintillators (e.g., plastic, liquid, and inorganic) show a reduced light yield for increased local energy deposition densities, an effect termed ionization quenching. The ionization quenching can reduce the light yield for low-energy protons by up to ∼20%. This work provides all necessary data for absolute spectral measurements of LPA protons with DRZ High scintillating screens, e.g., when used in the commonly applied Thomson parabola spectrometers. [ABSTRACT FROM AUTHOR]

The article critically discusses the concept of ›the mass‹ from the perspective of crowdsourcing application fields. It provides, also considering historic aspects, an overview of specific methods used in the field of citizen science and in digital humanities projects.

Foot health in zoo giraffe has been a topic of recent research, although little is known about the foot health of free-ranging giraffe. This study describes the foot shape and radiographic pathological changes in 27 young adult Nubian giraffe (Giraffa camelopardalis camelopardalis) from a translocation in Uganda (August 2017). Giraffe feet were observed to have a concave sole, the hoof wall was longest by the toe tip, and the weight-bearing surface of the foot was primarily along the periphery of the foot including hoof wall, parts of the heel, and the edge of the sole. Radiographs showed that pedal osteitis and sesamoid bone cysts were relatively uncommon (3/24 giraffe with osteitis, 1/24 giraffe with sesamoid cysts), and that no giraffe in the study had P3 joint osteoarthritis, P3 rotation, or P3 fractures. Radiographs consistently demonstrated a positive palmar/plantar angle with the sole of the hoof thicker at the heel than by the toe tip, with the non weight-bearing palmar/plantar angle measuring 1.6°- 4.3°. This is the first systematic review of foot shape and radiographs in free-ranging giraffe and demonstrates a low prevalence of foot pathologies. This study suggests qualitative differences in foot shape, foot health, radiographic anatomy, and foot pathologies when comparing free-ranging and zoo giraffe. Further research is needed to identify why these differences occur and whether husbandry modifications could help improve zoo giraffe foot health and prevent associated lameness.

The number of distressed refugees from the Arab world is relatively high in Germany and other host countries worldwide. For this specific population, substantial challenges and barriers have already been identified that hamper access to Germany's health care system. This study aims to contribute to this line of research by exploring the representation of depressive symptoms, both somatic and psychological, in order to inform clinicians about the most prevalent symptoms reported by Arabic-speaking refugee outpatients. Furthermore, this paper investigates the longstanding claim that mental health stigma fosters the expression of bodily distress. For these purposes, a total of 100 Arabic-speaking refugee outpatients, mostly Syrians, were recruited in Berlin, Germany. Somatic and psychological symptoms were assessed with the Patient Health Questionnaire (PHQ) 15 and 9, while stigma was assessed with the Brief Version of the Internalized Stigma of Mental Illness Scale (ISMI-10). Study results show that both somatic and psychological symptom severity was moderate while sleeping problems and energy loss were the most reported symptoms across both scales. Stigma was low and showed no association with somatic complaints in a multiple regression analysis, but was associated with more psychological symptoms. A principal factor extraction on the PHQ-15 items revealed five independent, somatic symptom clusters that were interpreted considering the rich poetic resources of the Arabic language. In conclusion, both somatic and psychological symptoms were commonly reported by Arabic-speaking refugees with symptoms of depression. Whereas, stigma does not seem to influence the expression of somatic symptoms, the present results provide first empirical indications for the relationship of symptom expression with the use of explanatory models and conceptualizations of mental illness within the Arabic culture and language. Future research efforts should be dedicated to enhancing our understanding of mental health care needs in this population as well as to exploring other mediators that might help explain the varying degree of somatic symptoms in depression across cultures.

Simulated altitude (normobaric hypoxia, NH) is used to study physiologic hypoxia responses of altitude. However, several publications show differences in physiological responses between NH and hypobaric conditions at altitude (hypobaric hypoxia, HH). The causality for these differences is controversially discussed. One theory is that the lower air density and environmental pressure in HH compared to NH lead to lower alveolar pressure and therefore lower oxygen diffusion in the lung. We hypothesized that, if this theory is correct, due to physical laws (Hagen-Poiseuille, Boyle), resistance respectively air compression (Boyle) at expiration should be lower, expiratory flow higher, and therefore peak flow and maximum expiratory flow (MEF) 75–50 increased in hypobaric hypoxia (HH) vs. normobaric hypoxia (NH). To prove the hypothesis of differences in respiratory flow as a result of lower alveolar pressure between HH and NH, we performed spirography in NH at different simulated altitudes and the corresponding altitudes in HH. In a cross over study, 6 healthy subjects (2 f/4 m, 28.3 ± 8.2 years, BMI: 23.2 ± 1.9) performed spirography as part of spiroergometry in a normobaric hypoxic room at a simulated altitude of 2800 m and after a seven-hour hike on a treadmill (average incline 14%, average walking speed 1.6 km/h) to the simulated summit of Mauna Kea at 4200 m. After a two-month washout, we repeated the spirometry in HH on the start and top of the Mauna Kea hiking trail, HI/USA. Comparison of NH (simulated 4200 m) and HH at 4200 m resulted in increased pulmonary ventilation during exercise (VE) (11.5%, p < 0.01), breathing-frequency (7.8%, p < 0.01), peak expiratory flow PEF (13.4%, p = 0.028), and MEF50 (15.9%, p = 0.028) in HH compared to NH, whereas VO2max decreased by 2%. At 2800 m, differences were only trendy, and at no altitude were differences in volume parameters. Spirography expresses higher mid expiratory flows and peak flows in HH vs. NH. This supports the theory of lower alveolar and small airway pressure due to a lower air density resulting in a lower resistance.