Consistency of convolutional neural networks in dermoscopic melanoma recognition: A prospective real-world study about the pitfalls of augmented intelligence.

BACKGROUND: Deep-learning convolutional neural networks (CNNs) have outperformed even experienced dermatologists in dermoscopic melanoma detection under controlled conditions. It remains unexplored how real-world dermoscopic image transformations affect CNN robustness. OBJECTIVES: To investigate the consistency of melanoma risk assessment by two commercially available CNNs to help formulate recommendations for current clinical use. METHODS: A comparative cohort study was conducted from January to July 2022 at the Department of Dermatology, University Hospital Basel. Five dermoscopic images of 116 different lesions on the torso of 66 patients were captured consecutively by the same operator without deliberate rotation. Classification was performed by two CNNs (CNN-1/CNN-2). Lesions were divided into four subgroups based on their initial risk scoring and clinical dignity assessment. Reliability was assessed by variation and intraclass correlation coefficients. Excisions were performed for melanoma suspicion or two consecutively elevated CNN risk scores, and benign lesions were confirmed by expert consensus (n = 3). RESULTS: 117 repeated image series of 116 melanocytic lesions (2 melanomas, 16 dysplastic naevi, 29 naevi, 1 solar lentigo, 1 suspicious and 67 benign) were classified. CNN-1 demonstrated superior measurement repeatability for clinically benign lesions with an initial malignant risk score (mean variation coefficient (mvc): CNN-1: 49.5(±34.3)%; CNN-2: 71.4(±22.5)%; p = 0.03), while CNN-2 outperformed for clinically benign lesions with benign scoring (mvc: CNN-1: 49.7(±22.7)%; CNN-2: 23.8(±29.3)%; p = 0.002). Both systems exhibited lowest score consistency for lesions with an initial malignant risk score and benign assessment. In this context, averaging three initial risk scores achieved highest sensitivity of dignity assessment (CNN-1: 94%; CNN-2: 89%). Intraclass correlation coefficients indicated 'moderate'-to-'good' reliability for both systems (CNN-1: 0.80, 95% CI:0.71-0.87, p < 0.001; CNN-2: 0.67, 95% CI:0.55-0.77, p < 0.001). CONCLUSIONS: Potential user-induced image changes can significantly influence CNN classification. For clinical application, we recommend using the average of three initial risk scores. Furthermore, we advocate for CNN robustness optimization by cross-validation with repeated image sets. TRIAL REGISTRATION: ClinicalTrials.gov (NCT04605822).

Nuclear Charge Radius of

Collinear laser spectroscopy was performed on the isomer of the aluminium isotope ^{26m}Al. The measured isotope shift to ^{27}Al in the 3s^{2}3p ^{2}P_{3/2}^{○}→3s^{2}4s ^{2}S_{1/2} atomic transition enabled the first experimental determination of the nuclear charge radius of ^{26m}Al, resulting in R_{c}=3.130(15) fm. This differs by 4.5 standard deviations from the extrapolated value used to calculate the isospin-symmetry breaking corrections in the superallowed ß decay of ^{26m}Al. Its corrected Ft value, important for the estimation of V_{ud} in the Cabibbo-Kobayashi-Maskawa matrix, is thus shifted by 1 standard deviation to 3071.4(1.0) s.

Discovery of Gamma Rays from the Quiescent Sun with HAWC.

We report the first detection of a TeV γ-ray flux from the solar disk (6.3σ), based on 6.1 years of data from the High Altitude Water Cherenkov (HAWC) observatory. The 0.5-2.6 TeV spectrum is well fit by a power law, dN/dE=A(E/1 TeV)^{-γ}, with A=(1.6±0.3)×10^{-12} TeV^{-1} cm^{-2} s^{-1} and γ=3.62±0.14. The flux shows a strong indication of anticorrelation with solar activity. These results extend the bright, hard GeV emission from the disk observed with Fermi-LAT, seemingly due to hadronic Galactic cosmic rays showering on nuclei in the solar atmosphere. However, current theoretical models are unable to explain the details of how solar magnetic fields shape these interactions. HAWC's TeV detection thus deepens the mysteries of the solar-disk emission.

Safety and immunogenicity of VPM1002 versus BCG in South African newborn babies: a randomised, phase 2 non-inferiority double-blind controlled trial.

BACKGROUND: Tuberculosis is a major public health problem worldwide. Immunisation with Mycobacterium bovis BCG vaccine is partially effective in infants, reducing the incidence of miliary and tuberculosis meningitis, but is less effective against pulmonary tuberculosis. We aimed to compare safety and immunogenicity of VPM1002-a recombinant BCG vaccine developed to address this gap-with BCG in HIV exposed and HIV unexposed newborn babies. METHODS: This double-blind, randomised, active controlled phase 2 study was conducted at four health centres in South Africa. Eligible neonates were aged 12 days or younger with a birthweight of 2·5-4·2 kg, and could be HIV exposed (seropositive mothers) or unexposed (seronegative mothers). Newborn babies were excluded if they had acute or chronic illness, fever, hypothermia, sepsis, cancer, or congenital malformation, or if they received blood products or immunosuppressive therapy. Participants were excluded if their mothers (aged ≥18 years) had active tuberculosis disease, diabetes, a history of immunodeficiency except for HIV, hepatitis B or syphilis seropositivity, received blood products in the preceding 6 months, any acute infectious disease, or any suspected substance abuse. Participants were randomly assigned to VPM1002 or BCG vaccination in a 3:1 ratio, stratified by HIV status using the random number generator function in SAS, using a block size of eight paticipants. The primary outcome was non-inferiority (margin 15%) of VPM1002 to BCG vaccine in terms of incidence of grade 3-4 adverse drug reactions or ipsilateral or generalised lymphadenopathy of 10 mm or greater in diameter by 12 months. The primary outcome was assessed in all vaccinated participants (safety population) at regular follow-up visits until 12 months after vaccination. Secondary immunogenicity outcomes were interferon-γ levels and percentages of multifunctional CD4+ and CD8+ T cells among all lymphocytes across the 12 month study period. The study was registered with ClinicalTrials.gov, NCT02391415. FINDINGS: Between June 4, 2015 and Oct 16, 2017, 416 eligible newborn babies were randomly assigned and received study vaccine. Seven (2%) of 312 participants in the VPM1002 group had a grade 3-4 vaccine-related adverse reaction or lymphadenopathy of 10 mm or greater in diameter compared with 34 (33%) of 104 participants in the BCG group (risk difference -30·45% [95% CI -39·61% to -21·28%]; pnon-inferiority<0·0001); VPM1002 was thus non-inferior to BCG for the primary outcome. Incidence of severe injection site reactions was lower with VPM1002 than BCG: scarring occurred in 65 (21%) participants in the VPM1002 group versus 77 (74%) participants in the BCG group (p<0·0001); ulceration occurred in one (<1%) versus 15 (14%; p<0·0001); and abscess formation occurred in five (2%) versus 23 (22%; p<0·0001). Restimulated IFNγ concentrations were lower in the VPM1002 group than the BCG group at week 6, week 12, month 6, and month 12. The percentage of multifunctional CD4+ T cells was higher in the VPM1002 group than the BCG group at day 14 but lower at week 6, week 12, month 6, and month 12. The percentage of multifunctional CD8+ T cells was lower in the VPM1002 group than the BCG group at week 6, week 12, and month 6, but did not differ at other timepoints. INTERPRETATION: VPM1002 was less reactogenic than BCG and was not associated with any serious safety concern. Both vaccines were immunogenic, although responses were higher with the BCG vaccine. VPM1002 is currently being studied for efficacy and safety in a multicentric phase 3 clinical trial in babies in sub-Saharan Africa. FUNDING: Serum Institute of India.

Nuclear Charge Radii of the Nickel Isotopes

Collinear laser spectroscopy is performed on the nickel isotopes ^{58-68,70}Ni, using a time-resolved photon counting system. From the measured isotope shifts, nuclear charge radii R_{c} are extracted and compared to theoretical results. Three ab initio approaches all employ, among others, the chiral interaction NNLO_{sat}, which allows an assessment of their accuracy. We find agreement with experiment in differential radii δ⟨r_{c}^{2}⟩ for all employed ab initio methods and interactions, while the absolute radii are consistent with data only for NNLO_{sat}. Within nuclear density functional theory, the Skyrme functional SV-min matches experiment more closely than the Fayans functional Fy(Δr,HFB).

Charge Radius of the Short-Lived

We present the first laser spectroscopic measurement of the neutron-rich nucleus ^{68}Ni at the N=40 subshell closure and extract its nuclear charge radius. Since this is the only short-lived isotope for which the dipole polarizability α_{D} has been measured, the combination of these observables provides a benchmark for nuclear structure theory. We compare them to novel coupled-cluster calculations based on different chiral two- and three-nucleon interactions, for which a strong correlation between the charge radius and dipole polarizability is observed, similar to the stable nucleus ^{48}Ca. Three-particle-three-hole correlations in coupled-cluster theory substantially improve the description of the experimental data, which allows to constrain the neutron radius and neutron skin of ^{68}Ni.

Multiple Galactic Sources with Emission Above 56 TeV Detected by HAWC.

We present the first catalog of gamma-ray sources emitting above 56 and 100 TeV with data from the High Altitude Water Cherenkov Observatory, a wide field-of-view observatory capable of detecting gamma rays up to a few hundred TeV. Nine sources are observed above 56 TeV, all of which are likely galactic in origin. Three sources continue emitting past 100 TeV, making this the highest-energy gamma-ray source catalog to date. We report the integral flux of each of these objects. We also report spectra for three highest-energy sources and discuss the possibility that they are PeVatrons.

[Influence of immunomodulators on urological imaging]. / Einfluss von Immunmodulatoren auf die urologische Bildgebung.

BACKGROUND: Immune checkpoint inhibitors (ICI) have led to great advances in the therapy of metastatic renal cell and urothelial carcinoma. Currently ICI are approved for the first-line therapy of cisplatin-unfit patients (Atezolizumab, Pembrolizumab) and second-line therapy in patients with metastasized urothelial cancer (Atezolizumab, Nivolumab, Pembrolizumab). For the therapy of metastasized RCC, Nivolumab is approved as a second-line therapy and in combination with the CTLA­4 antibody Ipilimumab as a first-line therapy. OBJECTIVES: What does the optimized radiological follow-up and therapy response assessment for ICI, which differ in their pathways from common chemotherapeutics and anti-angiogenetic drugs, look like? What strategies are needed to meet the upcoming challenges concerning interpretation of the acquired images? METHODS: A systematic literature search was carried out for urothelial and renal cell carcinoma. RESULTS: Immune-related response criteria have been introduced to better characterize the imaging changes occurring under ICI, as monitoring response to immunotherapy still relies on RECIST. CONCLUSIONS: To properly identify and predict response after treatment with ICI, additional studies with long-term follow-ups are needed. Because of the growing use of ICI, radiologists and urologist should be familiar with common imaging findings (such as pseudo progress) under immunotherapy to correctly interpret these findings in daily routine.

Laser Spectroscopy of Neutron-Rich Tin Isotopes: A Discontinuity in Charge Radii across the N=82 Shell Closure.

The change in mean-square nuclear charge radii δ⟨r^{2}⟩ along the even-A tin isotopic chain ^{108-134}Sn has been investigated by means of collinear laser spectroscopy at ISOLDE/CERN using the atomic transitions 5p^{2} ^{1}S_{0}→5p6 s^{1}P_{1} and 5p^{2} ^{3}P_{0}→5p6s ^{3}P_{1}. With the determination of the charge radius of ^{134}Sn and corrected values for some of the neutron-rich isotopes, the evolution of the charge radii across the N=82 shell closure is established. A clear kink at the doubly magic ^{132}Sn is revealed, similar to what has been observed at N=82 in other isotopic chains with larger proton numbers, and at the N=126 shell closure in doubly magic ^{208}Pb. While most standard nuclear density functional calculations struggle with a consistent explanation of these discontinuities, we demonstrate that a recently developed Fayans energy density functional provides a coherent description of the kinks at both doubly magic nuclei, ^{132}Sn and ^{208}Pb, without sacrificing the overall performance. A multiple correlation analysis leads to the conclusion that both kinks are related to pairing and surface effects.

[Active surveillance in prostate cancer]. / Active Surveillance beim Prostatakarzinom.

Prostate cancer remains among the most commonly diagnosed malignancies worldwide in men. In patients with low-risk prostate cancer, the risk of metastasis and mortality is very low; therefore, a tumor surveillance strategy can be used. In patients undergoing active surveillance, curative active therapy is postponed without compromising opportunities for cure until there is evidence of progression or the patient desires active therapy. The aim of active surveillance in prostate cancer patients is to minimize treatment-related toxicity without impairing patient survival. To maintain patients under active surveillance, the following criteria should be met: prostate-specific antigen (PSA) ≤10 ng/ml, Gleason score ≤6, cT1 or cT2a, ≤2 biopsy cores with <50% cancer involvement of every positive core. Follow-up in active surveillance patients is based on repeat biopsy, serial PSA measurements, and digital rectal examination.

Publisher Correction: Very-high-energy particle acceleration powered by the jets of the microquasar SS 433.

In this Letter, owing to a production error, the penultimate version of the PDF was published. The HTML version was always correct. The PDF has been corrected online.

Very-high-energy particle acceleration powered by the jets of the microquasar SS 433.

SS 433 is a binary system containing a supergiant star that is overflowing its Roche lobe with matter accreting onto a compact object (either a black hole or neutron star)1-3. Two jets of ionized matter with a bulk velocity of approximately 0.26c (where c is the speed of light in vacuum) extend from the binary, perpendicular to the line of sight, and terminate inside W50, a supernova remnant that is being distorted by the jets2,4-8. SS 433 differs from other microquasars (small-scale versions of quasars that are present within our own Galaxy) in that the accretion is believed to be super-Eddington9-11, and the luminosity of the system is about 1040 ergs per second2,9,12,13. The lobes of W50 in which the jets terminate, about 40 parsecs from the central source, are expected to accelerate charged particles, and indeed radio and X-ray emission consistent with electron synchrotron emission in a magnetic field have been observed14-16. At higher energies (greater than 100 gigaelectronvolts), the particle fluxes of γ-rays from X-ray hotspots around SS 433 have been reported as flux upper limits6,17-20. In this energy regime, it has been unclear whether the emission is dominated by electrons that are interacting with photons from the cosmic microwave background through inverse-Compton scattering or by protons that are interacting with the ambient gas. Here we report teraelectronvolt γ-ray observations of the SS 433/W50 system that spatially resolve the lobes. The teraelectronvolt emission is localized to structures in the lobes, far from the centre of the system where the jets are formed. We have measured photon energies of at least 25 teraelectronvolts, and these are certainly not Doppler-boosted, because of the viewing geometry. We conclude that the emission-from radio to teraelectronvolt energies-is consistent with a single population of electrons with energies extending to at least hundreds of teraelectronvolts in a magnetic field of about 16 microgauss.

The efficacy of a discontinuous graded exercise test in measuring peak oxygen uptake in children aged 8 to 10 years.

As children's natural activity patterns are highly intermittent in nature, and characterised by rapid changes from rest to vigorous physical activity, discontinuous exercise tests may be considered ecologically valid for this population group. This study compared the peak physiological responses from a discontinuous and continuous graded exercise test (GXT_D, GXT_C, respectively) during treadmill exercise in children. Twenty-one healthy children (9.6 ± 0.6 y) completed GXT_D and GXT_C in a randomised order, separated by 72-hours. Following each GXT, and after a 15-minute recovery, participants completed a verification test at 105% of the velocity attained at peak oxygen consumption (VO2peak). There were no differences in VO2peak (55.3 ± 8.2 cf. 54.4 ± 7.6 mL·kg-1·min-1) or maximal heart rate (202 ± 10 cf. 204 ± 8 b·min-1) between GXT_C and GXT_D, respectively (P>.05). Peak running speed (10.7 ± 0.9 cf. 12.1 ± 1.3 km·h-1) and respiratory exchange ratio (1.04 ± 0.05 cf. 0.92 ± 0.05) were however different between tests (P<.001). Although similar peak physiological values were revealed between GXT_C and the corresponding verification test (P>.05), VO2peak (53.3 ± 7.3 mL·kg-1·min-1) and heart rate (197 ± 13 b·min-1) were significantly lower in the GXT_D verification test (P<.05). In conclusion, a discontinuous GXT is an accurate measure of VO2peak in children aged 8 to 10 years and may be a valid alternative to a continuous GXT, despite its longer duration.

First report of robot-assisted transperineal fusion versus off-target biopsy in patients undergoing repeat prostate biopsy.

PURPOSE: To clarify the value of targeted versus off-target biopsies in men with a suspicion of prostate cancer (PC) and a visible lesion in multi-parametric magnetic resonance imaging (mpMRI) using transperineal robot-assisted biopsy. METHODS: Fifty-five consecutive men with one non-palpable suspicious lesion in mpMRI after negative 12-core transrectal ultrasound-guided biopsy were enrolled in 2014-2015. Lesions were scored using the Prostate Imaging Reporting and Data System. A robot-assisted system was utilized to collect four robot-assisted targeted transperineal biopsy cores (RA-TB) within the lesion using mpMRI-TRUS elastic fusion. Untargeted transperineal 14-core biopsy was performed only outside the lesion (RA-UB). Histological grade was compared in biopsies and available prostatectomy specimens. RESULTS: Overall, 34 of 55 patients (62%) were diagnosed with PC based on biopsy. 85% of cancers were clinically significant PC (csPC) defined as GS ≥ 7. 85% of biopsy-proven cancers were detected with RA-TB alone. RA-UB identified only one additional patient with csPC and lead to upgrading in five biopsy cases (14.7%). Pathological evaluation of 14 prostatectomy specimens showed upgrading in 2 patients (14.3%), while all other patients were correctly classified by RA-TB without need of additional RA-UB. Mean procedure duration was 43 (±6) min, and only minor complications according to Clavien-Dindo were recorded during 30-day follow-up. CONCLUSIONS: This is the first report of transperineal robot-assisted elastic mpMRI-TRUS fusion biopsy. RA-TB of positive MR lesions enabled reliable detection of csPC, while RA-UB in MRI-negative regions is of minor importance.

Histone deacetylase inhibitors interrupt HSP90•RASGRP1 and HSP90•CRAF interactions to upregulate BIM and circumvent drug resistance in lymphoma cells.

Histone deacetylase (HDAC) inhibitors, which are approved for the treatment of cutaneous T-cell lymphoma and multiple myeloma, are undergoing evaluation in other lymphoid neoplasms. How they kill susceptible cells is incompletely understood. Here, we show that trichostatin A, romidepsin and panobinostat induce apoptosis across a panel of malignant B cell lines, including lines that are intrinsically resistant to bortezomib, etoposide, cytarabine and BH3 mimetics. Further analysis traces the pro-apoptotic effects of HDAC inhibitors to increased acetylation of the chaperone heat shock protein 90 (HSP90), causing release and degradation of the HSP90 client proteins RASGRP1 and CRAF, which in turn leads to downregulation of mitogen-activated protein kinase pathway signaling and upregulation of the pro-apoptotic BCL2 family member BIM in vitro and in vivo. Importantly, these pro-apoptotic effects are mimicked by RASGRP1 small interfering RNA (siRNA) or HSP90 inhibition and reversed by overexpression of constitutively active MEK1 or siRNA-mediated downregulation of BIM. Collectively, these observations not only identify a new HSP90 client protein, RASGRP1, but also delineate a complete signaling pathway from HSP90 acetylation through RASGRP1 and CRAF degradation to BIM upregulation that contributes to selective cytotoxicity of HDAC inhibitors in lymphoid malignancies.

VEGFR-2 expression in HCC, dysplastic and regenerative liver nodules, and correlation with pre-biopsy Dynamic Contrast Enhanced CT.

PURPOSE: To evaluate whether VEGFR-2-expression in hepatocellular carcinoma (HCC), dysplastic (DLN) and regenerative liver nodules (RLN) correlates with pre-histology, in vivo Dynamic Contrast Enhanced-Computed Tomography (DCE-CT) data as VEGFR-2-expression affects prognosis and therapeutic options. MATERIALS AND METHODS: 34 patients (63.6±8.9years, 7 females) underwent liver biopsy or surgery due to suspected HCC or dysplastic nodules after DCE-CT between 2009 and 2015 with no previous chemo- or interventional therapy. Immunohistochemistry staining for VEGFR-2 was performed using Immunoreactive-Remmele-Stegner-Score (IRS) for quantification. A 128-row CT-scanner was used for DCE-CT with assessment of perfusion parameters blood flow (BF), blood volume (BV), arterial liver perfusion (ALP), portal venous perfusion (PVP), and hepatic perfusion index (HPI). RESULTS: Histology confirmed HCC (n=10), DLN (n=7) and RLN (n=34). Mean IRS for VEGFR-2 in HCCs was 9.1±3.0, 7.3±1.6 for DLN and 5.2±2.8 for RLN (p=0.0004 for HCC vs. RLN). Perfusion values varied significantly between all three groups for BF and HPI (p<0.001 and p<0.0001) and for BV in HCC vs. RLN (p<0.0001) and DLN vs. RLN (p=0.0019). Strong correlations between VEGFR-2-IRS and perfusion parameters were observed for BF in HCC (r=0.88, p<0.01) and HPI in HCC and DLN (r=0.85, p<0.04; r=0.9, p<0.01). CONCLUSION: Immunostaining revealed different VEGFR-2-expression levels in HCC, dysplastic and regenerative liver nodules. Perfusion markers blood flow, blood volume and hepatic perfusion index correlated well with VEGFR-2-immunostaining. This non-invasive discrimination between regenerative and dysplastic/HCC nodules might open new perspectives for diagnosis, therapy planning, and anti-VEGFR therapy monitoring.

Publisher's Note: Isomer Shift and Magnetic Moment of the Long-Lived 1/2

This corrects the article DOI: 10.1103/PhysRevLett.116.182502.

Isomer Shift and Magnetic Moment of the Long-Lived 1/2

Collinear laser spectroscopy is performed on the _{30}^{79}Zn_{49} isotope at ISOLDE-CERN. The existence of a long-lived isomer with a few hundred milliseconds half-life is confirmed, and the nuclear spins and moments of the ground and isomeric states in ^{79}Zn as well as the isomer shift are measured. From the observed hyperfine structures, spins I=9/2 and I=1/2 are firmly assigned to the ground and isomeric states. The magnetic moment µ (^{79}Zn)=-1.1866(10)µ_{N}, confirms the spin-parity 9/2^{+} with a νg_{9/2}^{-1} shell-model configuration, in excellent agreement with the prediction from large scale shell-model theories. The magnetic moment µ (^{79m}Zn)=-1.0180(12)µ_{N} supports a positive parity for the isomer, with a wave function dominated by a 2h-1p neutron excitation across the N=50 shell gap. The large isomer shift reveals an increase of the intruder isomer mean square charge radius with respect to that of the ground state, δ⟨r_{c}^{2}⟩^{79,79m}=+0.204(6) fm^{2}, providing first evidence of shape coexistence.