The tumor suppressor kinase DAPK3 drives tumor-intrinsic immunity through the STING-IFN-ß pathway.

Evasion of host immunity is a hallmark of cancer; however, mechanisms linking oncogenic mutations and immune escape are incompletely understood. Through loss-of-function screening of 1,001 tumor suppressor genes, we identified death-associated protein kinase 3 (DAPK3) as a previously unrecognized driver of anti-tumor immunity through the stimulator of interferon genes (STING) pathway of cytosolic DNA sensing. Loss of DAPK3 expression or kinase activity impaired STING activation and interferon (IFN)-ß-stimulated gene induction. DAPK3 deficiency in IFN-ß-producing tumors drove rapid growth and reduced infiltration of CD103+CD8α+ dendritic cells and cytotoxic lymphocytes, attenuating the response to cancer chemo-immunotherapy. Mechanistically, DAPK3 coordinated post-translational modification of STING. In unstimulated cells, DAPK3 inhibited STING K48-linked poly-ubiquitination and proteasome-mediated degradation. After cGAMP stimulation, DAPK3 was required for STING K63-linked poly-ubiquitination and STING-TANK-binding kinase 1 interaction. Comprehensive phospho-proteomics uncovered a DAPK3-specific phospho-site on the E3 ligase LMO7, critical for LMO7-STING interaction and STING K63-linked poly-ubiquitination. Thus, DAPK3 is an essential kinase for STING activation that drives tumor-intrinsic innate immunity and tumor immune surveillance.

BATF and IRF4 cooperate to counter exhaustion in tumor-infiltrating CAR T cells.

The transcription factors nuclear factor of activated T cells (NFAT) and activator protein 1 (AP-1; Fos-Jun) cooperate to promote the effector functions of T cells, but NFAT in the absence of AP-1 imposes a negative feedback program of T cell hyporesponsiveness (exhaustion). Here, we show that basic leucine zipper ATF-like transcription factor (BATF) and interferon regulatory factor 4 (IRF4) cooperate to counter T cell exhaustion in mouse tumor models. Overexpression of BATF in CD8+ T cells expressing a chimeric antigen receptor (CAR) promoted the survival and expansion of tumor-infiltrating CAR T cells, increased the production of effector cytokines, decreased the expression of inhibitory receptors and the exhaustion-associated transcription factor TOX and supported the generation of long-lived memory T cells that controlled tumor recurrence. These responses were dependent on BATF-IRF interaction, since cells expressing a BATF variant unable to interact with IRF4 did not survive in tumors and did not effectively delay tumor growth. BATF may improve the antitumor responses of CAR T cells by skewing their phenotypes and transcriptional profiles away from exhaustion and towards increased effector function.

The cool brown dwarf Gliese 229 B is a close binary.

Owing to their similarities with giant exoplanets, brown dwarf companions of stars provide insights into the fundamental processes of planet formation and evolution. From their orbits, several brown dwarf companions are found to be more massive than theoretical predictions given their luminosities and the ages of their host stars1-3. Either the theory is incomplete or these objects are not single entities. For example, they could be two brown dwarfs each with a lower mass and intrinsic luminosity1,4. The most problematic example is Gliese 229 B (refs. 5,6), which is at least 2-6 times less luminous than model predictions given its dynamical mass of 71.4 ± 0.6 Jupiter masses (MJup) (ref. 1). We observed Gliese 229 B with the GRAVITY interferometer and, separately, the CRIRES+ spectrograph at the Very Large Telescope. Both sets of observations independently resolve Gliese 229 B into two components, Gliese 229 Ba and Bb, settling the conflict between theory and observations. The two objects have a flux ratio of 0.47 ± 0.03 at a wavelength of 2 µm and masses of 38.1 ± 1.0 and 34.4 ± 1.5 MJup, respectively. They orbit each other every 12.1 days with a semimajor axis of 0.042 astronomical units (AU). The discovery of Gliese 229 BaBb, each only a few times more massive than the most massive planets, and separated by 16 times the Earth-moon distance, raises new questions about the formation and prevalence of tight binary brown dwarfs around stars.

Degassing of early-formed planetesimals restricted water delivery to Earth.

The timing of delivery and the types of body that contributed volatiles to the terrestrial planets remain highly debated1,2. For example, it is unknown if differentiated bodies, such as that responsible for the Moon-forming giant impact, could have delivered substantial volatiles3,4 or if smaller, undifferentiated objects were more probable vehicles of water delivery5-7. Here we show that the water contents of minerals in achondrite meteorites (mantles or crusts of differentiated planetesimals) from both the inner and outer portions of the early Solar System are ≤2 µg g-1 H2O. These are among the lowest values ever reported for extraterrestrial minerals. Our results demonstrate that differentiated planetesimals efficiently degassed before or during melting. This finding implies that substantial amounts of water could only have been delivered to Earth by means of unmelted material.

A highly distorted ultraelastic chemically complex Elinvar alloy.

The development of high-performance ultraelastic metals with superb strength, a large elastic strain limit and temperature-insensitive elastic modulus (Elinvar effect) are important for various industrial applications, from actuators and medical devices to high-precision instruments1,2. The elastic strain limit of bulk crystalline metals is usually less than 1 per cent, owing to dislocation easy gliding. Shape memory alloys3-including gum metals4,5 and strain glass alloys6,7-may attain an elastic strain limit up to several per cent, although this is the result of pseudo-elasticity and is accompanied by large energy dissipation3. Recently, chemically complex alloys, such as 'high-entropy' alloys8, have attracted tremendous research interest owing to their promising properties9-15. In this work we report on a chemically complex alloy with a large atomic size misfit usually unaffordable in conventional alloys. The alloy exhibits a high elastic strain limit (approximately 2 per cent) and a very low internal friction (less than 2 × 10-4) at room temperature. More interestingly, this alloy exhibits an extraordinary Elinvar effect, maintaining near-constant elastic modulus between room temperature and 627 degrees Celsius (900 kelvin), which is, to our knowledge, unmatched by the existing alloys hitherto reported.

Universal structure of dark matter haloes over a mass range of 20 orders of magnitude.

Cosmological models in which dark matter consists of cold elementary particles predict that the dark halo population should extend to masses many orders of magnitude below those at which galaxies can form1-3. Here we report a cosmological simulation of the formation of present-day haloes over the full range of observed halo masses (20 orders of magnitude) when dark matter is assumed to be in the form of weakly interacting massive particles of mass approximately 100 gigaelectronvolts. The simulation has a full dynamic range of 30 orders of magnitude in mass and resolves the internal structure of hundreds of Earth-mass haloes in as much detail as it does for hundreds of rich galaxy clusters. We find that halo density profiles are universal over the entire mass range and are well described by simple two-parameter fitting formulae4,5. Halo mass and concentration are tightly related in a way that depends on cosmology and on the nature of the dark matter. For a fixed mass, the concentration is independent of the local environment for haloes less massive than those of typical galaxies. Haloes over the mass range of 10-3 to 1011 solar masses contribute about equally (per logarithmic interval) to the luminosity produced by dark matter annihilation, which we find to be smaller than all previous estimates by factors ranging up to one thousand3.

NR4A transcription factors limit CAR T cell function in solid tumours.

T cells expressing chimeric antigen receptors (CAR T cells) targeting human CD19 (hCD19) have shown clinical efficacy against B cell malignancies1,2. CAR T cells have been less effective against solid tumours3-5, in part because they enter a hyporesponsive ('exhausted' or 'dysfunctional') state6-9 triggered by chronic antigen stimulation and characterized by upregulation of inhibitory receptors and loss of effector function. To investigate the function of CAR T cells in solid tumours, we transferred hCD19-reactive CAR T cells into hCD19+ tumour-bearing mice. CD8+CAR+ tumour-infiltrating lymphocytes and CD8+ endogenous tumour-infiltrating lymphocytes expressing the inhibitory receptors PD-1 and TIM3 exhibited similar profiles of gene expression and chromatin accessibility, associated with secondary activation of nuclear receptor transcription factors NR4A1 (also known as NUR77), NR4A2 (NURR1) and NR4A3 (NOR1) by the initiating transcription factor NFAT (nuclear factor of activated T cells)10-12. CD8+ T cells from humans with cancer or chronic viral infections13-15 expressed high levels of NR4A transcription factors and displayed enrichment of NR4A-binding motifs in accessible chromatin regions. CAR T cells lacking all three NR4A transcription factors (Nr4a triple knockout) promoted tumour regression and prolonged the survival of tumour-bearing mice. Nr4a triple knockout CAR tumour-infiltrating lymphocytes displayed phenotypes and gene expression profiles characteristic of CD8+ effector T cells, and chromatin regions uniquely accessible in Nr4a triple knockout CAR tumour-infiltrating lymphocytes compared to wild type were enriched for binding motifs for NF-κB and AP-1, transcription factors involved in activation of T cells. We identify NR4A transcription factors as having an important role in the cell-intrinsic program of T cell hyporesponsiveness and point to NR4A inhibition as a promising strategy for cancer immunotherapy.

A magnetar-powered X-ray transient as the aftermath of a binary neutron-star merger.

Mergers of neutron stars are known to be associated with short γ-ray bursts1-4. If the neutron-star equation of state is sufficiently stiff (that is, the pressure increases sharply as the density increases), at least some such mergers will leave behind a supramassive or even a stable neutron star that spins rapidly with a strong magnetic field5-8 (that is, a magnetar). Such a magnetar signature may have been observed in the form of the X-ray plateau that follows up to half of observed short γ-ray bursts9,10. However, it has been expected that some X-ray transients powered by binary neutron-star mergers may not be associated with a short γ-ray burst11,12. A fast X-ray transient (CDF-S XT1) was recently found to be associated with a faint host galaxy, the redshift of which is unknown13. Its X-ray and host-galaxy properties allow several possible explanations including a short γ-ray burst seen off-axis, a low-luminosity γ-ray burst at high redshift, or a tidal disruption event involving an intermediate-mass black hole and a white dwarf13. Here we report a second X-ray transient, CDF-S XT2, that is associated with a galaxy at redshift z = 0.738 (ref. 14). The measured light curve is fully consistent with the X-ray transient being powered by a millisecond magnetar. More intriguingly, CDF-S XT2 lies in the outskirts of its star-forming host galaxy with a moderate offset from the galaxy centre, as short γ-ray bursts often do15,16. The estimated event-rate density of similar X-ray transients, when corrected to the local value, is consistent with the event-rate density of binary neutron-star mergers that is robustly inferred from the detection of the gravitational-wave event GW170817.

Misprogramming of glucose metabolism impairs recovery of hippocampal slices from neuronal GLT-1 knockout mice and contributes to excitotoxic injury through mitochondrial superoxide production.

We have previously reported a failure of recovery of synaptic function in the CA1 region of acute hippocampal slices from mice with a conditional neuronal knockout (KO) of GLT-1 (EAAT2, Slc1A2) driven by synapsin-Cre (synGLT-1 KO). The failure of recovery of synaptic function is due to excitotoxic injury. We hypothesized that changes in mitochondrial metabolism contribute to the heightened vulnerability to excitotoxicity in the synGLT-1 KO mice. We found impaired flux of carbon from 13C-glucose into the tricarboxylic acid cycle in synGLT-1 KO cortical and hippocampal slices compared with wild-type (WT) slices. In addition, we found downregulation of the neuronal glucose transporter GLUT3 in both genotypes. Flux of carbon from [1,2-13C]acetate, thought to be astrocyte-specific, was increased in the synGLT-KO hippocampal slices but not cortical slices. Glycogen stores, predominantly localized to astrocytes, are rapidly depleted in slices after cutting, and are replenished during ex vivo incubation. In the synGLT-1 KO, replenishment of glycogen stores during ex vivo incubation was compromised. These results suggest both neuronal and astrocytic metabolic perturbations in the synGLT-1 KO slices. Supplementing incubation medium during recovery with 20 mM D-glucose normalized glycogen replenishment but had no effect on recovery of synaptic function. In contrast, 20 mM non-metabolizable L-glucose substantially improved recovery of synaptic function, suggesting that D-glucose metabolism contributes to the excitotoxic injury in the synGLT-1 KO slices. L-lactate substitution for D-glucose did not promote recovery of synaptic function, implicating mitochondrial metabolism. Consistent with this hypothesis, phosphorylation of pyruvate dehydrogenase, which decreases enzyme activity, was increased in WT slices during the recovery period, but not in synGLT-1 KO slices. Since metabolism of glucose by the mitochondrial electron transport chain is associated with superoxide production, we tested the effect of drugs that scavenge and prevent superoxide production. The superoxide dismutase/catalase mimic EUK-134 conferred complete protection and full recovery of synaptic function. A site-specific inhibitor of complex III superoxide production, S3QEL-2, was also protective, but inhibitors of NADPH oxidase were not. In summary, we find that the failure of recovery of synaptic function in hippocampal slices from the synGLT-1 KO mouse, previously shown to be due to excitotoxic injury, is caused by production of superoxide by mitochondrial metabolism.

Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study.

BACKGROUND: Amivantamab plus carboplatin-pemetrexed (chemotherapy) with and without lazertinib demonstrated antitumor activity in patients with refractory epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) in phase I studies. These combinations were evaluated in a global phase III trial. PATIENTS AND METHODS: A total of 657 patients with EGFR-mutated (exon 19 deletions or L858R) locally advanced or metastatic NSCLC after disease progression on osimertinib were randomized 2 : 2 : 1 to receive amivantamab-lazertinib-chemotherapy, chemotherapy, or amivantamab-chemotherapy. The dual primary endpoints were progression-free survival (PFS) of amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy. During the study, hematologic toxicities observed in the amivantamab-lazertinib-chemotherapy arm necessitated a regimen change to start lazertinib after carboplatin completion. RESULTS: All baseline characteristics were well balanced across the three arms, including by history of brain metastases and prior brain radiation. PFS was significantly longer for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy [hazard ratio (HR) for disease progression or death 0.48 and 0.44, respectively; P < 0.001 for both; median of 6.3 and 8.3 versus 4.2 months, respectively]. Consistent PFS results were seen by investigator assessment (HR for disease progression or death 0.41 and 0.38 for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy, respectively; P < 0.001 for both; median of 8.2 and 8.3 versus 4.2 months, respectively). Objective response rate was significantly higher for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (64% and 63% versus 36%, respectively; P < 0.001 for both). Median intracranial PFS was 12.5 and 12.8 versus 8.3 months for amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy versus chemotherapy (HR for intracranial disease progression or death 0.55 and 0.58, respectively). Predominant adverse events (AEs) in the amivantamab-containing regimens were hematologic, EGFR-, and MET-related toxicities. Amivantamab-chemotherapy had lower rates of hematologic AEs than amivantamab-lazertinib-chemotherapy. CONCLUSIONS: Amivantamab-chemotherapy and amivantamab-lazertinib-chemotherapy improved PFS and intracranial PFS versus chemotherapy in a population with limited options after disease progression on osimertinib. Longer follow-up is needed for the modified amivantamab-lazertinib-chemotherapy regimen.

Nano-compositional imaging of the lanthanum silicide system at THz wavelengths.

Terahertz scattering-type scanning near-field optical microscopy (THz-sSNOM) provides a noninvasive way to probe the low frequency conductivity of materials and to characterize material compositions at the nanoscale. However, the potential capability of atomic compositional analysis with THz nanoscopy remains largely unexplored. Here, we perform THz near-field imaging and spectroscopy on a model rare-earth alloy of lanthanum silicide (La-Si) which is known to exhibit diverse compositional and structural phases. We identify subwavelength spatial variations in conductivity that is manifested as alloy microstructures down to much less than 1 µm in size and is remarkably distinct from the surface topography of the material. Signal contrasts from the near-field scattering responses enable mapping the local silicon/lanthanum content differences. These observations demonstrate that THz-sSNOM offers a new avenue to investigate the compositional heterogeneity of material phases and their related nanoscale electrical as well as optical properties.

The relationship between repeated measurements of HbA1c and risk of coronary events among the common haptoglobin phenotype groups: the Action for Health in Diabetes (Look AHEAD) study.

BACKGROUND: In the ACCORD study, participants with the haptoglobin (Hp) 2-2 phenotype and glycated hemoglobin (HbA1c) ≥ 8.0% had a higher risk of coronary artery disease (CAD) compared to those with HbA1c 7.0-7.9%. However, this association was not observed in participants without the Hp2-2 phenotype. The optimal glycemic target for CAD prevention for the Hp phenotypes remains uncertain and may vary based on demographic and clinical factors. OBJECTIVE: To investigate how reaching clinically relevant HbA1c targets relates to the risk of CAD in different Hp phenotype groups among a diverse cohort of individuals with T2DM (the Look AHEAD study, HbA1c ≤ 11% at baseline). METHODS: Cox regression models with time-varying covariables were used to quantify the association between time-varying achieved HbA1c (< 6.5%, 6.5-6.9%, and ≥ 8.0% compared to 7.0-7.9%), updated at years 1-4, 6, 8, and 10, and incident CAD in the Hp2-2 (n = 1,587) and non-Hp2-2 (n = 2,944) phenotypes separately. Further pre-specified subgroup analyses by age, sex, history of cardiovascular disease (CVD), race, and diabetes duration were performed in each Hp phenotype group separately. RESULTS: Compared with HbA1c 7.0-7.9%, having HbA1c < 6.5% was associated with a 29% lower CAD risk among participants with the non-Hp2-2 phenotype (adjusted HR 0.71, 95% CI 0.55-0.90). In subgroup analyses, this association was present in participants with the non-Hp2-2 phenotype who were male (0.60, 0.44-0.83), who did not have a history of CVD (0.65, 0.47-0.90), who were aged ≥ 65 years (0.64, 0.44-0.94), who were White (0.68, 0.51-0.91), or who had diabetes duration > 10 years (0.58, 0.35-0.95). HbA1c ≥ 8.0% was associated with CAD risk only among participants with the Hp2-2 phenotype who had a history of CVD (1.79, 1.00-3.20). No associations were found between the other HbA1c targets and CAD risk when participants with the Hp2-2 phenotype were grouped together or divided into subgroups. CONCLUSION: The differences in our results compared to our previous findings may be due to variations in the study populations and factors associated with weight loss, making it difficult to draw definitive conclusions. Our current findings should be considered in the context of hypothesis generation, and ideally, will encourage additional research in this field.

Mild obesity does not affect perinatal outcome in gestational carrier cycles.

STUDY QUESTION: Does BMI of gestational carriers (GCs) affect perinatal outcomes after embryo transfer? SUMMARY ANSWER: Overweight and class I obesity in GCs does not affect the rate of good perinatal outcomes. WHAT IS KNOWN ALREADY: The use of GCs is increasing, but uniform guidance regarding optimal BMI for GCs is lacking. Women with obesity who conceive without fertility treatment or through autologous or donor in vitro fertilization are at higher risk of adverse maternal and fetal outcomes, but data on obesity in GCs are very limited. STUDY DESIGN, SIZE, DURATION: We performed a retrospective cohort study of 1121 GC cycles from January 2015 to December 2020 at US Fertility, the largest national partnership of fertility practices in the USA. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: All GC cycles performed at a large network of fertility practices were reviewed. Same-sex partners undergoing co-IVF were excluded. The primary outcome was good perinatal outcome from the first embryo transfer, defined as a singleton live birth at ≥37 weeks of gestation with birth weight between 2500 and 4000 g. Secondary outcome measures included frequencies of live birth, clinical pregnancy, miscarriage, full-term birth, low birth weight, large for gestational age, and cesarean delivery. A generalized linear model (log-binomial) was used for each to compare outcomes across BMI groups using normal BMI (20-24.9 kg/m2) as the reference group. Risk ratios and 95% CIs were estimated for each category group relative to normal BMI. MAIN RESULTS AND THE ROLE OF CHANCE: We identified 1121 cycles in which GCs underwent first embryo transfer, of which 263 (23.5%) were in GCs with BMI >30. Demographics and reproductive history for GCs did not differ by BMI groups. The age of intended parents, use of frozen eggs, and fresh embryo transfers were higher with increasing BMI group. There were no statistically significant associations between BMI and good perinatal outcomes, live birth, clinical pregnancy, biochemical, spontaneous abortion, or low birth weight. However, among live births, higher BMI was significantly associated with birth by cesarean (P = 0.015) and large for gestational age infants (P = 0.023). LIMITATIONS, REASONS FOR CAUTION: This was a retrospective study, and there may be unmeasured confounders. The number of patients with BMI <20 or ≥35 was small, limiting the power for these groups. We were not able to assess all maternal and fetal outcomes. WIDER IMPLICATIONS OF THE FINDINGS: In this study, we did not identify any significant impact of BMI on the chances of having a good perinatal outcome. Prior research studies have been inconsistent and this is the largest study to date. STUDY FUNDING/COMPETING INTEREST(S): No external funding was received for this work. The authors do not have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Ferroelectric Semimetals with α-Bi/SnSe van der Waals Heterostructures and Their Topological Currents.

We show that proximity effects can be utilized to engineer van der Waals heterostructures (vdWHs) displaying semimetallic spin-ferroelectricity locking, where ferroelectricity and semimetallic spin states are confined to different layers, but are correlated by means of proximity effects. Our findings are supported by first principles calculations involving α-Bi/SnSe bilayers. We show that such systems support ferroelectrically switchable nonlinear anomalous Hall effect originating from large Berry curvature dipoles as well as direct and inverse spin Hall effects with giant bulk spin-charge interconversion efficiencies. The giant efficiencies are consequences of the proximity-induced semimetallic nature of low energy electron states, which are shown to behave as two-dimensional pseudo-Weyl fermions by means of symmetry analysis and first principles calculations as well as direct angle-resolved photoemission spectroscopy measurements.

Discovery of New Isotopes

Using the fusion-evaporation reaction ^{106}Cd(^{58}Ni,4n)^{160}Os and the gas-filled recoil separator SHANS, two new isotopes _{76}^{160}Os and _{74}^{156}W have been identified. The α decay of ^{160}Os, measured with an α-particle energy of 7080(26) keV and a half-life of 201_{-37}^{+58} µs, is assigned to originate from the ground state. The daughter nucleus ^{156}W is a ß^{+} emitter with a half-life of 291_{-61}^{+86} ms. The newly measured α-decay data allow us to derive α-decay reduced widths (δ^{2}) for the N=84 isotones up to osmium (Z=76), which are found to decrease with increasing atomic number above Z=68. The reduction of δ^{2} is interpreted as evidence for the strengthening of the N=82 shell closure toward the proton drip line, supported by the increase of the neutron-shell gaps predicted in theoretical models.

Establishing the utility of multi-platform liquid biopsy by integrating the CSF methylome and proteome in CNS tumours.

BACKGROUND: Liquid biopsy represents a major development in cancer research, with significant translational potential. Similarly, it is increasingly recognized that multi-omic molecular approaches are a powerful avenue through which to understand complex and heterogeneous disease biology. We hypothesize that merging these two promising frontiers of cancer research will improve the discriminatory capacity of current models and allow for improved clinical utility. METHODS: We have compiled a cohort of patients with glioblastoma, brain metastasis, and primary central nervous system lymphoma. Cell-free methylated DNA immunoprecipitation (cfMeDIP) and shotgun proteomic profiling was obtained from the cerebrospinal fluid (CSF) of each patient and used to build tumour-specific classifiers. RESULTS: We show that the DNA methylation and protein profiles of cerebrospinal fluid can be integrated to fully discriminate lymphoma from its diagnostic counterparts with perfect AUC of 1 (95% confidence interval 1-1) and 100% specificity, significantly outperforming single-platform classifiers. CONCLUSIONS: We present the most specific and accurate CNS lymphoma classifier to date and demonstrates the synergistic capability of multi-platform liquid biopsies. This has far-reaching translational utility for patients with newly diagnosed intra-axial brain tumours.

Population-based epidemiological projections of rheumatoid arthritis in Germany until 2040.

OBJECTIVES: Our aim was to conduct a population-based projection to estimate the number of rheumatoid arthritis (RA) cases in Germany until 2040. METHOD: Data obtained from a report published in 2017 (doi:10.20364/VA-17.08) were used for future prediction analysis. The data were originally collected by the German Central Institute for Statutory Health Insurance. We used the illness-death model to estimate future numbers of RA cases, considering nine possible scenarios based on different incidence and mortality rates. RESULTS: In the baseline scenario, the number of women with RA is projected to increase by 417 000 cases and men by 179 000 cases by 2040, compared with 2015. Peak numbers of cases are concentrated in the 70-80-year-old age group, particularly among women. In the most favourable scenario (scenario 2), assuming a decreasing incidence, the total number of RA cases is projected to rise by 284 000 by 2040, reflecting a 38% relative increase from 2015 to 2040. The least favourable scenario (scenario 9), assuming an increasing incidence, projects a significant burden on the healthcare system. The total number of RA cases is expected to rise by 1.16 million by 2040, marking a substantial 158% relative increase from 2015 to 2040. CONCLUSIONS: Our research emphasizes a discernible trend: with an ageing society, improving treatment effectiveness, and declining all-cause mortality, we anticipate a rise in the absolute numbers of RA cases in Germany in the coming years. Our models robustly support this viewpoint, underscoring impending challenges for healthcare systems. Addressing these challenges demands multifaceted interventions.

Higher baseline subcortical net water uptake in computed tomography predicts malignant middle cerebral artery infarction in patients with acute ischemic stroke.

AIM: The objective of this study was to assess the predictive performance of net water uptake (NWU) based on the Alberta stroke program early CT score (ASPECTS) from different ASPECT regions in relation to the development of malignant middle cerebral artery (MCA) infarction. MATERIAL AND METHODS: Patients with acute ischemic stroke (AIS) of the MCA territory were retrospectively enrolled between January 2019 and July 2022. Patients were divided into two groups according to the follow-up CT after 24-48 hours: malignant and nonmalignant infarction. NWUs were measured on diverse ASPECT regions on admission non-contrast CT, namely affected ASPECTS-NWU (af-ASPECTS-NWU), subcortical ASPECTS-NWU (sc-ASPECTS-NWU), and cortical ASPECTS-NWU (c-ASPECTS-NWU). Baseline characteristics were collected for univariate analyses and multivariate regression analyses to explore the independent risk factors for malignant infarction. Receiver operating characteristic (ROC) curves were plotted and compared. RESULTS: patients were included in the final analysis. Malignant MCA infarction was achieved in 42 (27.45%) patients and nonmalignant was 111 (72.55%). Compared with the nonmalignant infarction group, higher baseline National Institute of Health stroke scale (NIHSS) score, af-ASPECTS-NWU, c-ASPECTS-NWU, sc-ASPECTS-NWU, and lower ASPECTS were noted in the malignant infarction group (all P < 0.001). Multivariate logistic regression showed that only baseline sc-ASPECTS-NWU (>3.6%) was a positive factor for malignant MCA infarction. The ROC analysis indicated the highest predictive value of sc-ASPECTS-NWU for indicating malignant infarction with the area under ROC curve (AUC) 0.91. CONCLUSION: Higher baseline sc-ASPECTS-NWU was a quantitative predictor for malignant MCA infarction in patients with AIS, which could be helpful for treatment decisions.

Magnetic resonance imaging (MRI)-based intratumoral and peritumoral radiomics for prognosis prediction in glioma patients.

AIM: The purpose of this study was to identify robust radiological features from intratumoral and peritumoral regions, evaluate MRI protocols, and machine learning methods for overall survival stratification of glioma patients, and explore the relationship between radiological features and the tumour microenvironment. MATERIAL AND METHODS: A retrospective analysis was conducted on 163 glioma patients, divided into a training set (n=113) and a testing set (n=50). For each patient, 2135 features were extracted from clinical MRI. Feature selection was performed using the Minimum Redundancy Maximum Relevance method and the Random Forest (RF) algorithm. Prognostic factors were assessed using the Cox proportional hazards model. Four machine learning models (RF, Logistic Regression, Support Vector Machine, and XGBoost) were trained on clinical and radiological features from tumour and peritumoral regions. Model evaluations on the testing set used receiver operating characteristic curves. RESULTS: Among the 163 patients, 96 had an overall survival (OS) of less than three years postsurgery, while 67 had an OS of more than three years. Univariate Cox regression in the validation set indicated that age (p=0.003) and tumour grade (p<0.001) were positively associated with the risk of death within three years postsurgery. The final predictive model incorporated 13 radiological and 7 clinical features. The RF model, combining intratumor and peritumor radiomics, achieved the best predictive performance (AUC = 0.91; ACC = 0.86), outperforming single-region models. CONCLUSION: Combined intratumoral and peritumoral radiomics can improve survival prediction and have potential as a practical imaging biomarker to guide clinical decision-making.

Classification of breast edema on T2-weighted imaging for predicting sentinel lymph node metastasis and biological behavior in breast cancer.

OBJECTIVE: To determine whether preoperative classification of breast edema on T2-weighted imaging (T2WI) is useful for predicting sentinel lymph node (SLN) metastasis and biological behavior in patients with early-stage breast cancer. METHODS: This retrospective study involved 341 women with breast cancer who underwent breast MRI from January 2019 to March 2022. Breast edema was scored on a scale of 1-4 on T2WI (1, no edema; 2, peritumoral edema; 3, prepectoral edema; and 4, subcutaneous edema). A logistic regression model was employed for univariate and multivariate analyses. A clinicopathological model was established using independent influencing factors identified in the multivariate analyses, excluding breast edema score (BES). Subsequently, BES was incorporated into this model to establish a combined BES model. The AUC and Delong test were used to examine the additional predictive value of the BES. RESULTS: Logistic regression analysis showed that breast edema was an independent risk factor for SLN metastasis. The combined BES model significantly improved the predictive performance of SLN metastasis compared with the clinicopathological model alone (AUC, 0.77 vs. 0.71; p=0.005). In addition, the BES was significantly positively correlated with the tumor diameter (p<0.001), histologic grade (p=0.001), Ki-67 index (p<0.001), and non-luminal subtypes (p<0.001). CONCLUSION: The BES on T2WI is useful for predicting SLN metastasis. A higher grade of breast edema is associated with breast cancer aggressiveness and increases the probability of SLN metastasis.