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Burnout, Depression, and Diminished Well-Being among Physicians
B cells enhance IL-1 beta driven invasiveness in triple negative breast cancer
Finerenone in Heart Failure with Preserved Ejection Fraction
Comparison of management options for spontaneous bleeding into soft tissues in patients with COVID-19
Case 2-2025: A 21-Year-Old Man with Loss of Consciousness and a Fall
High-resolution X-ray phase-contrast tomography of human placenta with different wavefront markers
Abstract Phase-contrast micro-tomography ( $$\upmu$$ CT) with synchrotron radiation can aid in the differentiation of subtle density variations in weakly absorbing soft tissue specimens. Modulation-based imaging (MBI) extracts phase information from the distortion of reference patterns, generated by periodic or randomly structured wavefront markers (e.g., gratings or sandpaper). The two approaches have already found application for the virtual inspection of biological samples. Here, we perform high-resolution $$\upmu$$ CT scans of an unstained human placenta specimen, using MBI with both a 2D grating and sandpaper as modulators, as well as conventional propagation-based imaging (PBI). The 3D virtual representation of placenta offers a valuable tool for analysing its intricate branching villous network and vascular structure, providing new insights into its complex architecture. Within this study, we assess reconstruction quality achieved with all three evaluated phase-contrast methods. Both MBI datasets are processed with the Unified Modulated Pattern Analysis (UMPA) model, a pattern-matching algorithm. In order to evaluate the benefits and suitability of MBI for virtual histology, we discuss how the complexities of the technique influence image quality and correlate the obtained volumes to 2D techniques, such as conventional histology and X-ray fluorescence (XRF) elemental maps.
Centrophilic retrotransposon integration via CENH3 chromatin in Arabidopsis
Fracture Prevention with Infrequent Zoledronate in Women 50 to 60 Years of Age
A hybrid critical channels and optimal feature subset selection framework for EEG fatigue recognition
Publisher Correction: Preliminary investigation on the establishment of a new meibomian gland obstruction model and gene expression
Self-referential belief shares common neural correlates with general belief
Abstract Belief processing and self-referential processing have been consistently associated with cortical midline structures, and cortical regions such as the vmPFC have been implicated in general belief processing. The neural correlates of self-referential belief are yet to be investigated. In this fMRI study, we presented 120 statements with trait adjectives to N = 27 healthy participants, who subsequently judged whether they believed these trait adjectives applied to themselves, a close person, or a public person. Thereafter, participants rated their certainty in this judgment. Expectedly, self-referential processing evoked a large cluster in the vmPFC, ACC, and dmPFC. For belief, we found a cluster in the vmPFC, ACC, and amPFC during statement presentation, partially overlapping with that for self-referential processing. The cluster for self-belief vs. disbelief was similar in location and size to that for general belief processing. For uncertainty, we found dmPFC activation. We replicated vmPFC involvement in belief processing and found a common neural correlate for belief and self-belief in the vmPFC. Furthermore, we replicated the role of the dmPFC in uncertainty, supporting a dual neural process model of belief and certainty.
HLA-I aberrations in cutaneous T-cell lymphoma
Daratumumab with lenalidomide as maintenance after transplant in newly diagnosed multiple myeloma: the AURIGA study
Abstract No randomized trial has directly compared daratumumab and lenalidomide (D-R) maintenance with standard-of-care lenalidomide (R) alone after transplant. Herein, we report the primary results of the phase 3 AURIGA study evaluating D-R vs R maintenance in patients with newly diagnosed multiple myeloma (NDMM) who had very good or better partial response, were minimal residual disease (MRD)-positive (10–5) and anti-CD38–naïve after transplant. Two hundred patients were randomly assigned (1:1) to D-R (n = 99) or R (n = 101) maintenance for up to 36 cycles. The MRD-negative (10–5) conversion rate by 12 months from start of maintenance (primary end point) was significantly higher for D-R than R (50.5% vs 18.8%; odds ratio [OR], 4.51; 95% confidence interval [CI], 2.37-8.57; P < .0001). MRD-negative (10–6) conversion rate was similarly higher with D-R (23.2% vs 5.0%; OR, 5.97; 95% CI, 2.15-16.58; P = .0002). At median follow-up (32.3 months), D-R achieved a higher overall MRD-negative (10–5) conversion rate (D-R, 60.6% vs R, 27.7%; OR, 4.12; 95% CI, 2.26-7.52; P < .0001) and complete response rate or better (75.8% vs 61.4%; OR, 2.00; 95% CI, 1.08-3.69; P = .0255) vs R. Progression-free survival (PFS) favored D-R vs R (hazard ratio, 0.53; 95% CI, 0.29-0.97); estimated 30-month PFS rates were 82.7% for D-R and 66.4% for R. Incidences of grade 3/4 cytopenias (54.2% vs 46.9%) and infections (18.8% vs 13.3%) were slightly higher with D-R than R. In conclusion, D-R maintenance achieved a higher MRD-negative conversion rate and improved PFS after transplant vs R, with no new safety concerns. This trial was registered at www.clinicaltrials.gov as #NCT03901963.
Genetic alteration of class I HLA in cutaneous T-cell lymphoma
Abstract Abnormalities involving class I HLA are frequent in many lymphoma subtypes but have not yet been extensively studied in cutaneous T-cell lymphomas (CTCLs). We characterized the occurrence of class I HLA abnormalities in 65 patients with advanced mycosis fungoides or Sézary syndrome. Targeted DNA sequencing, including coverage of HLA loci, revealed at least 1 HLA abnormality in 26 of 65 patients (40%). Twelve unique somatic HLA mutations were identified across 9 patients, and loss of heterozygosity or biallelic loss of HLA was found to affect 24 patients. Although specific HLA alleles were commonly disrupted, these events did not associate with a decrease in the total class I HLA expression. Genetic events preferentially disrupted HLA alleles capable of presenting greater numbers of putative neoantigens. HLA abnormalities co-occurred with other genetic immune evasion events and were associated with worse progression-free survival. Single-cell analyses demonstrated that HLA abnormalities were frequently subclonal. Through analysis of serial samples, we observed that disrupting class I HLA events change dynamically over the disease course. The dynamics of HLA disruption are highlighted in a patient who received pembrolizumab and in whom resistance to pembrolizumab was associated with the elimination of an HLA mutation. Overall, our findings show that genomic class I HLA abnormalities are common in advanced CTCL and may be an important consideration in understanding the effects of immunotherapy in CTCL.
Combined targeted modality in cHL: a risky bet?
Brentuximab vedotin, nivolumab, doxorubicin, and dacarbazine for advanced-stage classical Hodgkin lymphoma
Abstract Treatment options for stage I/II bulky and advanced-stage disease have recently extensively changed. For decades in North America, ABVD (doxorubicin hydrochloride [Adriamycin], bleomycin sulfate, vinblastine sulfate, and dacarbazine) has been a frontline standard-of-care option for patients with advanced classical Hodgkin lymphoma (cHL). Recent data on combining brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine demonstrated improved overall survival compared with ABVD but increased adverse events (AEs). We hypothesized that replacing vinblastine with nivolumab (brentuximab vedotin and nivolumab [AN] + doxorubicin and dacarbazine [AD]; AN+AD) may improve efficacy and safety. This phase 2, open-label multipart, multicenter study enrolled patients with treatment-naive stage II bulky or III/IV cHL. Patients received ≤6 cycles of AN+AD; granulocyte-colony stimulating factor (G-CSF) prophylaxis was optional, per institutional guidelines. At the time of planned analysis (N = 57), complete response (CR) and objective response rates were 88% (95% confidence interval [CI], 76.3-94.9) and 93% (95% CI, 83.0-98.1), respectively. With a median follow-up of 24.2 months (95% CI, 23.4-26.9), the 2-year progression-free survival rate was 88% (95% CI, 75.7-94.6); 88% (95% CI, 75.7-94.6) had a response lasting >2 years. Most common grade ≥3 treatment-related AEs were alanine aminotransferase increased (11%) and neutropenia (9%); 44% had treatment-related peripheral sensory neuropathy (grade 1/2, 40%; grade 3, 4%). No febrile neutropenia occurred; 49% received G-CSF prophylaxis. AN+AD led to a high CR rate and favorable safety profile. Further evaluation of programmed death receptor 1 inhibitor and CD30 antibody–drug conjugate combination regimens in frontline advanced-stage cHL is warranted. This trial was registered at www.clinicaltrials.gov as #NCT03646123 and www.clinicaltrialsregister.eu as #EudraCT 2020-004027-17.
IFN-I promotes T-cell–independent immunity and RBC autoantibodies via modulation of B-1 cell subsets in murine SCD
Abstract The pathophysiology of sickle cell disease (SCD) is characterized by hemolytic anemia and vaso-occlusion, although its impact on the adaptive immune responses remains incompletely understood. To comprehensibly profile the humoral immune responses, we immunized SCD mice with T-cell–independent (TI) and T-cell–dependent (TD) antigens (Ags). Our study showed that SCD mice have significantly enhanced type 2 TI (TI-2) immune responses in a manner dependent on the level of type I interferons (IFN-I), while maintaining similar or decreased TD immune responses depending on the route of Ag administration. Consistent with the enhanced TI-2 immune responses in SCD mice, the frequencies of B-1b cells (B-1 cells in humans), a major cell type responding to TI-2 Ags, were significantly increased in both the peritoneal cavity and spleens of SCD mice and in the blood of patients with SCD. In support of expanded B-1 cells, elevated levels of anti–red blood cell (anti-RBC) autoantibodies were detected in both SCD mice and patients. Both the levels of TI-2 immune responses and anti-RBC autoantibodies were significantly reduced after IFN-I receptor (IFNAR) antibody blockades and in IFNAR1–deficient SCD mice. Moreover, the alterations of B-1 cell subsets were reversed in IFNAR1–deficient SCD mice, uncovering a critical role for IFN-I in the enhanced TI-2 immune responses and the increased production of anti-RBC autoantibodies by modulating the innate B-1 cell subsets in SCD. Overall, our study provides experimental evidence that the modulation of B-1 cells and IFN-I can regulate TI immune responses and the levels of anti-RBC autoantibodies in SCD.
Comparison of progression risk of monoclonal gammopathy of undetermined significance by method of detection
Abstract Monoclonal gammopathy of undetermined significance (MGUS) is an asymptomatic premalignant disorder. The current standard of care is not to screen for MGUS, so it is often incidentally diagnosed in the clinic. It is unknown whether the outcomes of screened vs clinically detected MGUS differ. We compared the progression risk between screened vs clinical MGUS cohorts and assessed whether the MGUS detection method affected risk prediction of established clinical factors (score). We included 379 screened MGUS cases from the Olmsted County population-based study and 1384 patients with MGUS diagnosed during routine clinical evaluation at Mayo Clinic. Median follow-up time for the screened vs clinical cohort was 26.6 and 40.1 years, respectively. Accounting for death as a competing risk, the cumulative incidence of progression at 25 years was similar in the screened (11.1% [95% confidence interval [CI], 8.3-14.8]) vs clinical (10.1% [95% CI, 8.6-11.8]) MGUS cohorts, even when stratified by sex, age, or the baseline MGUS risk score. Overall, 0.9 (95% CI, 0.6-1.2) of patients with screened MGUS vs 1.0 (95% CI, 0.9-1.2) of those with clinically detected MGUS experienced disease progression for every 100 person-years of follow-up. MGUS detection method did not modify the association between MGUS risk score and progression risk (pinteraction = 0.217) and did not add to known risk factors for progression (likelihood ratio test; P = .839). Here, we show that progression risk among patients with screened vs clinically detected heavy-chain MGUS was similar. Future studies are needed to assess whether tailored follow-up of patients with screened MGUS affects clinical outcomes.