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Natural killer (NK) cells are innate lymphoid cells (ILCs) contributing to immune responses to microbes and tumors. Historically, their classification hinged on a limited array of surface protein markers. Here, we used single-cell RNA sequencing (scRNA-seq) and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) to dissect the heterogeneity of NK cells. We identified three prominent NK cell subsets in healthy human blood: NK1, NK2 and NK3, further differentiated into six distinct subgroups. Our findings delineate the molecular characteristics, key transcription factors, biological functions, metabolic traits and cytokine responses of each subgroup. These data also suggest two separate ontogenetic origins for NK cells, leading to divergent transcriptional trajectories. Furthermore, we analyzed the distribution of NK cell subsets in the lung, tonsils and intraepithelial lymphocytes isolated from healthy individuals and in 22 tumor types. This standardized terminology aims at fostering clarity and consistency in future research, thereby improving cross-study comparisons.

Abstract: The antiapoptotic protein, myeloid cell leukemia-1 (Mcl-1), contributes to the pathophysiology of acute myeloid leukemia (AML) and certain B-cell malignancies. Tumor dependence on Mcl-1 is associated with resistance to venetoclax. Voruciclib, an oral cyclin-dependent kinase (CDK) inhibitor targeting CDK9, indirectly decreases Mcl-1 protein expression and synergizes with venetoclax in preclinical models. This dose escalation study evaluated voruciclib in patients with previously treated hematologic malignancies. Initially, voruciclib was administered daily, continuously, on a 28-day cycle (group 1). After 2 patients with prior allogeneic stem cell transplantation had a dose-limiting toxicity (DLT) of interstitial pneumonitis at 100 mg, voruciclib administration was changed to days 1 to 14 of a 28-day cycle (group 2). Forty patients, 21 with AML and 19 with B-cell malignancies, were enrolled. Patients had a median of 3 prior lines of therapy (range, 1-8). Dose escalation in group 2 was stopped at 200 mg, a dose that achieved plasma concentrations sufficient for target inhibition, without DLTs observed. The most common adverse events were diarrhea (30%), nausea (25%), anemia (22%), fatigue (22%), constipation (17%), dizziness (15%), and dyspnea (15%). In AML, 1 patient achieved a morphologic leukemia-free state, and 2 had stable disease. Voruciclib treatment led to a decrease in MCL1 messenger RNA expression, downregulation of myelocytomatosis (MYC) and NF-κB transcriptional gene sets, and reduced phosphorylation of RNA polymerase 2. Voruciclib on intermittent dosing was well tolerated, with no DLTs, paving the way for evaluation of the combination of voruciclib with venetoclax for patients with previously treated AML. This trial was registered at www.clinicaltrials.gov as #NCT03547115.

BACKGROUND: Cancer increases the risk of developing TB disease; however, there are limited data on the magnitude of risk by cancer type and timing after diagnosis of cancer in low TB incidence settings. METHODS: We conducted a nested case-control study of persons in Quebec between 1993 and 2017, including people with TB disease and matched controls. Conditional logistic regression was used to estimate adjusted odds ratios (aORs) of developing TB among people with cancer overall, by sub-type, and by time from cancer to TB diagnosis. RESULTS: There were 4,283 people with TB disease and 268,420 matched controls. The median age for people with TB disease and controls was respectively 46 years (IQR 30–67) and 36 years (24–47). Prior exposure to cancer was associated with TB disease (aOR 6.3, 95% CI 5.3–7.6). The risk of TB diagnosis was highest within 3 months of cancer diagnosis (aOR 26.6, 95% CI 19.6–36.2), with 60% of diagnoses of TB disease occurring within 6 months of cancer diagnosis. CONCLUSION: Risk of TB varies over time and by cancer type. Screening and treatment should be considered for potentially preventable TB (diagnosed more than 6 months post-cancer), particularly in those with respiratory, haematologic, and head and neck cancers.

Abstract Dendritic cells (DCs) are crucial for initiating protective immune responses and have also been implicated in the generation and regulation of Foxp3+ regulatory T cells (Treg cells). Here, we show that in the lamina propria of the small intestine, the alternative NF-κB family member RelB is necessary for the differentiation of cryptopatch and isolated lymphoid follicle-associated DCs (CIA-DCs). Moreover, single-cell RNA sequencing reveals a RelB-dependent signature in migratory DCs in mesenteric lymph nodes favoring DC-Treg cell interaction including elevated expression and release of the chemokine CCL22 from RelB-deficient conventional DCs (cDCs). In line with the key role of CCL22 to facilitate DC-Treg cell interaction, RelB-deficient DCs have a selective advantage to interact with Treg cells in an antigen-specific manner. In addition, DC-specific RelB knockout animals show increased total Foxp3+ Treg cell numbers irrespective of inflammatory status. Consequently, DC-specific RelB knockout animals fail to mount protective Th2-dominated immune responses in the intestine after infection with Heligmosomoides polygyrus bakeri. Thus, RelB expression in cDCs acts as a rheostat to establish a tolerogenic set point that is maintained even during strong type 2 immune conditions and thereby is a key regulator of intestinal homeostasis.

We conducted a nationwide, randomized controlled trial to evaluate the impact of Healing Choices, a novel interactive education and treatment decision program rooted in the self-regulation theory framework, on decisional conflict and psychological distress at 2-month post-intervention in women with early-stage breast cancer. Patients were randomized to receive the National Cancer Institutes standard print material (control) or standard print material plus Healing Choices (the intervention). The final sample at 2-month post-intervention consisted of N = 388 participants (intervention: n = 197; control: n = 191). There were no significant differences in decisional conflict or its subscales; however, psychological distress was higher in the intervention group (16.09 ± 10.25) than in the control group (14.37 ± 8.73) at follow-up, B = 1.88, 95% CI [-0.03, 3.80], t(383) = 1.94, p = .05. Upon further examination, we found that engagement with the intervention was low-41%-prompting as-treated analyses, which showed no difference in distress between users and nonusers and a positive impact of Healing Choices on decisional conflict: decisional support subscale: users (35.36 ± 15.50) versus nonusers (39.67 ± 15.99), B = -4.31 (s.e. = 2.09), p = .04. Multiple recommendations for moving ahead stem from this work: (i) intent-to-treat analyses appeared to cause distress, cautioning against interventions that may lead to information overload; (ii) engagement with the intervention is low and future work needs to focus on increasing engagement and monitoring it throughout the study; and (iii) in studies with low engagement, as-treated analyses are critical.

Background Biomarkers that change in response to nintedanib in subjects with idiopathic pulmonary fibrosis (IPF) would be valuable. We investigated the effects of nintedanib on circulating biomarkers in subjects with IPF in the INMARK trial. Methods Subjects with IPF were randomised 1:2 to receive nintedanib 150 mg twice daily or placebo for 12 weeks, after which all patients received open-label nintedanib for 40 weeks. Fold changes in adjusted mean levels of circulating biomarkers were analysed using a linear mixed model for repeated measures. Results 346 subjects were treated (116 randomised to nintedanib, 230 to placebo). Surfactant protein D (SP-D) and cancer antigen 125 (CA-125), markers of epithelial injury, decreased in subjects treated with nintedanib versus placebo. Fold changes from baseline in SP-D at week 12 corresponded to a 4% decrease and 3% increase in the nintedanib and placebo groups, respectively (ratio 0.94, 95% CI 0.89–0.99; p=0.024). Fold changes in CA-125 at week 12 corresponded to a 22% decrease and 4% increase in the nintedanib and placebo groups, respectively (ratio 0.75, 95% CI 0.71–0.81; p

Immune checkpoint inhibitors (ICI) are increasingly used in combination. To understand the effects of different ICI categories, we characterized changes in circulating autoantibodies in patients enrolled in the E4412 trial (NCT01896999) of brentuximab vedotin (BV) plus ipilimumab, BV plus nivolumab, or BV plus ipilimumab-nivolumab for Hodgkin Lymphoma. Cycle 2 Day 1 (C2D1) autoantibody levels were compared to pre-treatment baseline. Across 112 autoantibodies tested, we generally observed increases in ipilimumab-containing regimens, with decreases noted in the nivolumab arm. Among 15 autoantibodies with significant changes at C2D1, all nivolumab cases exhibited decreases, with more than 90% of ipilimumab-exposed cases showing increases. Autoantibody profiles also showed differences according to immune-related adverse event (irAE) type, with rash generally featuring increases and liver toxicity demonstrating decreases. We conclude that dynamic autoantibody profiles may differ according to ICI category and irAE type. These findings may have relevance to clinical monitoring and irAE treatment.

Aim: Extracorporeal cardiopulmonary resuscitation (ECPR) by veno-arterial extracorporeal membrane oxygenation (VA-ECMO) during refractory cardiac arrest presents significant medical and psychological challenges for healthcare providers. Beyond managing cardiac arrest and preparing for potential coronary angiography, the ECMO circuit must be assembled and primed under strictly sterile conditions, contributing to additional psychological stress and potential delays in ECMO cannulation. This pragmatic study thought to evaluate whether pre-assembled and pre-primed ECMO circuits (pre-primed group) maintain sterility over a 21-day period, expedite ECMO initiation in ECPR patients and alleviate the psychological burden on the ECPR team, compared to newly assembled and primed ECMO circuits (on-demand group). Methods: In a prospective manner, ECMO circuits were either pre-assembled and pre-primed under sterile conditions, maintained for 21 days with culture samples taken every seventh day, or newly assembled and primed during the acute emergency situation. The transition from on-demand assembly and priming of ECMO circuits to pre-primed ECMO circuits occurred on January 1st, 2021. The interval between patients’ arrival in the cardiac catheterization laboratory and the initiation of ECMO was recorded and retrospectively compared between the two treatment groups. The ECPR team, comprising experienced cardiologists and nurses, was prospectively surveyed using the modified Perceived Stress Questionnaire (PSQ-20). Results: All aseptically pre-assembled and pre-primed ECMO circuits demonstrated sterile cultures for aerobic and anaerobic microorganisms as well as fungal agents over the 21-day period: 0/120 positive cultures (0 %, 95 % CI for binomial probability 0–0.03). The time to ECMO initiation was significantly reduced in the pre-primed group compared to the on-demand group: 13 [IQR 9–17] versus 31 [IQR 27–44] minutes, P

Background Children with chronic illness perform poorer at school, and school well-being (SWB) may mediate this association. We investigated the association between chronic illness and three domains of SWB in children in first grade. Methods Data from a German population-based prospective cohort study were used. Children with chronic illness were identified via their preschool health examination and follow-up parent surveys during first grade. Children were grouped as either (i) having current special health care needs (SHCN), (ii) having at least one physician diagnosis of a chronic illness but no current SHCN, or (iii) being healthy. SWB was assessed at the end of first grade and measured by the Questionnaire for the Assessment of Emotional and Social School Experiences of First and Second Grade Primary School Children. Based on SWB theory and previous frameworks, the following subscales were used: School-Related Self-Concept, Social Integration, and Joy of Learning. The sum score for each subscale was converted into area-transformed T-values (mean 50 and standard deviation 10). Associations between chronic illness groups and SWB subscales were investigated by multivariable linear regression models. Effect estimates were adjusted for potential confounding variables and standardized mean differences (SMD) were calculated. Results Of the 1,490 children included, 15% had current SHCN and 37% had a physician diagnosis of a chronic illness but no current SHCN. Compared to healthy children, children with SHCN had lower scores for the School-Related Self-Concept and the Joy of Learning subscale (SMD −0.18 for both) but not for the Social Integration subscale. In contrast, children with a chronic condition but no SHCN had lower scores only for the Social Integration subscale (SMD −0.12). Conclusions Primary school students with a chronic illness with or without SHCN have lower SWB in some domains compared to their healthy peers. SWB may be a mediator in the association between chronic illness and poor school performance.

Introdução: A Leucemia Linfocítica Aguda (LLA) consiste na proliferação exacerbada de células B ou T imaturas, cujo clone maligno origina-se na medula óssea ou no sistema linfático. Os sintomas clássicos decorrem da infiltração medular por células neoplásicas e pela supressão de linhagens hematopoiéticas. No entanto, complicações raras como a hipercalcemia secundária a LLA podem ocorrer. Relato de caso: Paciente masculino, 58 anos, encaminhado para avaliação hematológica devido à plaquetopenia severa. Em abril de 2024, apresentou febre intermitente e tremores, sendo diagnosticado com dengue na UBS de Santa Rosa-RS, com contagem plaquetária de 87.000/μL. O tratamento foi com manejo sintomático. Em maio, retornou com adinamia, fraqueza, dor torácica, perda de peso e dor lombar, associadas a plaquetopenia (57.000/μL) e anemia severa (Hb 6,0 g/dL), necessitando de hidratação intravenosa e transfusão de hemácias. Após alta hospitalar, o paciente retornou apresentando dispneia, dor torácica, palidez, melena e inapetência. Uma endoscopia digestiva alta revelou úlceras e gastrite, tratadas com pantoprazol. Com a persistência dos sintomas, foi readmitido em junho no Hospital de Caridade Astrogildo de Azevedo (HCAA) com piora da anemia e plaquetopenia (33.000/μL), além de adenopatia cervical bilateral ao exame físico, recebendo nova transfusão de hemácias. Durante esta internação, foi diagnosticada hipercalcemia secundária, com níveis séricos alcançando 11,5 mg/dL. Durante o período de investigação hematológica no HCAA, a análise da medula óssea revelou uma população clonal de linfócitos B com imunofenótipos aberrantes. O paciente também apresentou perda de peso, totalizando 17 kg durante o período. Iniciou-se então o esquema de quimioterapia de indução HYPER-CVAD e Pamidronato 90 mg EV para redução da carga tumoral e correção da hipercalcemia. Atualmente, no 14° dia de indução do tratamento, o paciente apresenta pancitopenia severa (Leucócitos 100 e 10% de blastos), sem febre, com diminuição das adenopatias cervicais. Discussão: A hipercalcemia na LLA é um evento raro, possivelmente decorrente da produção ectópica de proteínas relacionadas ao paratormônio (PTHrP) pelas células leucêmicas, aumento da reabsorção óssea e liberação de cálcio, ou secreção de citocinas que estimulam os osteoclastos. Em adultos, a incidência de LLA é menor, com um aumento gradual em idosos. A hipercalcemia também é uma complicação rara na LLA e associada a um prognóstico desfavorável. A hipercalcemia no sistema neurológico, pode causar confusão mental, letargia e, em casos mais severos, coma. No trato gastrointestinal, provoca náuseas, vômitos, constipação, dor abdominal e anorexia. Nos rins, a sobrecarga renal pode resultar em nefrocalcinose e insuficiência renal aguda e, também, causar sintomas como poliúria e polidipsia. No sistema cardiovascular, pode resultar em hipertensão, arritmias e redução da contratilidade miocárdica. O sistema musculoesquelético pode apresentar dor óssea intensa e muscular, além de aumento do risco de osteoporose e fraturas. Outros sintomas menos comuns, mas ainda relevantes, incluem prurido e alterações no humor, como depressão e ansiedade. Essas manifestações adicionais ressaltam a complexidade e a gravidade da hipercalcemia em pacientes com LLA. Conclusão: A hipercalcemia na LLA é uma complicação rara e grave, exigindo diagnóstico e tratamento rápidos para evitar danos sistêmicos severos e potencialmente fatais.

INTRODUCTION The United States Preventive Services Task Force (USPSTF) guidelines recommend lung cancer screening (LCS), with an annual low dose-computed tomography scan of the chest, for individuals who meet age [...], PURPOSE Many individuals who are eligible for lung cancer screening have comorbid conditions complicating their shared decision-making conversations with physicians. The goal of our study was to better understand how primary care physicians (PCPs) factor comorbidities into their evaluation of the risks and benefits of lung cancer screening and into their shared decision-making conversations with patients. METHODS We conducted semistructured interviews by videoconference with 15 PCPs to assess the extent of shared decision-making practices and explore their understanding of the intersection of comorbidities and lung cancer screening, and how that understanding informed their clinical approach to this population. RESULTS We identified 3 themes. The first theme was whether to discuss or not to discuss lung cancer screening. PCPs described taking additional steps for individuals with complex comorbidities to decide whether to initiate this discussion and used subjective clinical judgment to decide whether the conversation would be productive and beneficial. PCPs made mental assessments that factored in the patient's health, life expectancy, quality of life, and access to support systems. The second theme was that shared decision making is not a simple discussion. When PCPs did initiate discussions about lung cancer screening, although some believed they could provide objective information, others struggled with personal biases. The third theme was that ultimately, the decision to be screened was up to the patient. Patients had the final say, even if their decision was discordant with the PCP's advice. CONCLUSIONS Shared decision-making conversations about lung cancer screening differed substantially from the standard for patients with complex comorbidities. Future research should include efforts to characterize the risks and benefits of LCS in patients with comorbidities to inform guidelines and clinical application. Key words: lung cancer screening; preventive medicine; comorbidities; multimorbidity; clinical reasoning; judgment; paternalism; beneficence; personal autonomy; risk-benefit assessment; life expectancy; quality of life; counseling; education of patients; shared decision making; patient-centered care; holistic health; primary care; practice-based research

Summary: Immune cells express an incredible variety of proteins; by measuring combinations of these, cell types influencing disease can be precisely identified. We developed terraFlow, a platform that defines cell subsets exhaustively by combinatorial protein expression. Using high-parameter checkpoint-focused and function-focused panels, we studied classical Hodgkin’s lymphoma (cHL), where systemic T cells have not been investigated in detail. terraFlow revealed immune perturbations in patients, including elevated activated, exhausted, and interleukin (IL)-17+ phenotypes, along with diminished early, interferon (IFN)γ+, and tumor necrosis factor (TNF)+ T cells before treatment; many perturbations remained after treatment. terraFlow identified more disease-associated differences than other tools, often with better predictive power, and included a non-gating approach, eliminating time-consuming and subjective manual thresholds. It also reports a method to identify the smallest set of markers distinguishing study groups. Our results provide mechanistic support for past reports of immune deficiency in cHL and demonstrate the value of terraFlow in immunotherapy and biomarker studies.

Abstract Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil‐derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI 1291583. Five phase I trials of BI 1291583 in healthy subjects are presented: a single‐rising‐dose study (NCT03414008) and two multiple‐rising‐dose studies (NCT03868540 and NCT04866160) assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of BI 1291583; a food effect study (NCT03837964); and a drug–drug interaction study (NCT03890887) of BI 1291583 and itraconazole. BI 1291583 was safe and well tolerated across the doses tested in these trials. Most adverse events (AEs) were mild or moderate in intensity, with no serious AEs, AEs of special interest or deaths reported in any trial. Drug‐related skin exfoliation was not reported more frequently in subjects treated with BI 1291583 compared with placebo. BI 1291583 was readily absorbed, and pharmacokinetics were supra‐proportional over the dose ranges assessed. Additionally, BI 1291583 inhibited CatC in a dose‐dependent manner, inhibited downstream NE activity, and decreased PR3 levels. No food effect was observed. Co‐administration of multiple doses of itraconazole increased BI 1291583 exposure approximately twofold. Due to these promising phase I results, a multinational phase II program of BI 1291583 in adults with bronchiectasis is ongoing (Airleaf™ [NCT05238675], Clairafly™ [NCT05865886], and Clairleaf™ [NCT05846230]).

Background We used data from the INMARK trial to investigate associations between circulating biomarkers of extracellular matrix (ECM) turnover, inflammation and epithelial dysfunction and disease progression in subjects with idiopathic pulmonary fibrosis (IPF). Methods Subjects with IPF and forced vital capacity (FVC) ≥80% predicted were randomised 1:2 to receive nintedanib 150 mg twice daily or placebo for 12 weeks followed by open-label nintedanib for 40 weeks. Associations between baseline biomarker levels and the proportion of subjects with disease progression (decline in FVC ≥10% predicted or death) over 52 weeks were assessed in subjects randomised to placebo using logistic regression. Associations between baseline demographic/clinical characteristics and biomarker levels and disease progression over 52 weeks were analysed using multivariate models. Results Of 230 subjects who received placebo for 12 weeks then open-label nintedanib for 40 weeks, 70 (30.4%) had disease progression over 52 weeks. Baseline levels of CRPM (C-reactive protein (CRP) degraded by matrix metalloproteinase (MMP)-1/8), C3M (collagen 3 degraded by MMP-9), CRP, KL-6 (Krebs von den Lungen-6) and SP-D (surfactant protein D) were not significantly associated with disease progression over 52 weeks in analyses corrected for multiple comparisons. In models including only baseline demographic/clinical characteristics, 61.2–64.2% of subjects were correctly classified as having or not having disease progression over 52 weeks. When both demographic/clinical characteristics and biomarker levels were included in the models, 50.0–64.5% of the test set were correctly classified. Conclusions Among subjects with IPF and preserved FVC, multivariate models based on demographic/clinical characteristics and biomarker levels at baseline did not provide an accurate prediction of which patients would progress.