Natural killer (NK) cells are critical for both innate and adaptive immunity, and their effective regulation holds significant promise for tumor immunotherapy. The terminal maturation of NK cells is closely associated with enhanced effector functions, but the role of epigenetic mechanisms in this process remains incompletely understood. Here, we identify the histone methyltransferase EHMT2 as an epigenetic regulator that restrains NK cell maturation and function. EHMT2 expression is markedly downregulated upon cytokine activation in human NK cells and inversely correlated with effector gene expression across tissues and cancer types. NK cell-specific deletion of Ehmt2 in mice promotes terminal NK cell maturation, augmenting IFN-γ production and cytotoxicity both in vitro and in vivo. Integrated RNA-seq and H3K9me2 CUT&Tag profiling reveal that Ehmt2 loss reduces the repressive histone mark H3K9me2 and derepresses transcriptional programs associated with NK cell differentiation and cytotoxicity. Pharmacological inhibition of EHMT2 recapitulated these effects in both human umbilical cord blood (hUCB)-hematopoietic stem cell (HSC)-derived NK cells and peripheral blood NK cells, promoting terminal maturation and tumor cell killing. These findings define EHMT2-dependent H3K9me2 deposition as a key epigenetic barrier to NK cell effector programming and suggest that targeting EHMT2 may potentiate NK cell-based immunotherapies.

Reactivating quiescent tumor cells at the invasive margin are either eliminated by immune surveillance or expand through immune escape. The mechanisms underpinning phenotypic plasticity driving expansion leading to therapeutic resistance, dissemination, and recurrence remain elusive. Here we establish a metabolic licensing paradigm wherein reactive astrocytes awaken dormant glioblastoma cells and simultaneously confer immune evasion through intercellular mitochondrial transfer. Astrocyte-derived mitochondria, enriched with the one carbon metabolism enzyme SHMT2, deliver functional metabolic units that reprogram recipient glioma cells. This shuttled cargo fuels S adenosylmethionine production, driving m⁶A RNA methylation and release of paused RNA polymerase II over a specific set of genes. Ribosome biogenesis and focal adhesion pathways are selectively upregulated consequently, which enables rapid proliferation and immune resistance of tumour cells. Genetic ablation of astrocytic Shmt2 or pharmacological blockade of mitochondrial transfer suppresses quiescent cell reactivation and delays tumor progression. Our findings thus establish the astrocyte-mitochondria shuttle as a core vulnerability in glioblastomas, linking metabolic crosstalk to epitranscriptomic control of reactivation and immune escape.

Colorectal cancer (CRC) remains one of the most common solid malignancies in the Western population. Despite advances in screening, diagnostics, and treatment, there are still no highly specific tests for early diagnosis or biomarkers that can reliably identify high-risk patients or monitor disease progression more effectively than currently established tumor markers. The pathogenesis of CRC is closely associated with chronic inflammation, oxidative stress, and remodeling of the tumor microenvironment. The present study focuses on several biomarkers selected based on available literature data and their close association with these processes. LOX-1 (lectin-like oxidized low-density lipoprotein receptor-1), RAGE (receptor for advanced glycation end products), HMGB1 (high mobility group box 1), and matrix metalloproteinase-19 (MMP-19) are involved in the regulation of inflammatory signaling pathways, angiogenesis, and extracellular matrix degradation. The aim of this study was to test the hypothesis that the expression of these markers is significantly increased in patients with CRC compared with healthy controls.

The study included intestinal tissue samples obtained from 34 patients with CRC and 21 control subjects who underwent intestinal resection at our institution for non-neoplastic and non-inflammatory conditions. In CRC patients, three tissue compartments were analyzed - macroscopically normal tissue, the tumor transition zone, and tumor tissue. Samples were processed using immunohistochemical methods, and marker positivity was assessed across several cellular populations.

Statistically significant differences in the expression of selected markers were identified between the control group and patients with CRC. LOX-1 demonstrated increased expression in the epithelial and vascular structures of tumor tissue. RAGE expression was elevated in vascular structures and within the tumor transition zone, suggesting its involvement in the inflammatory tumor microenvironment. MMP-19 expression was most pronounced at the tumor-normal tissue interface, consistent with its role in extracellular matrix remodeling and tumor invasion.

Our findings support the involvement of the investigated markers in the pathogenesis of CRC. Their expression may contribute not only to a better understanding of CRC biology but also to the identification of potential prognostic biomarkers and therapeutic targets.

A boy in early adolescence was diagnosed with left-sided congenital pulmonary airway malformation (CPAM) at birth and remained asymptomatic until early adolescence, when he presented with dry cough, right-sided chest pain and breathlessness on exertion. Imaging showed right-sided pleural effusion with pulmonary nodules and skeletal metastases. Thoracoscopic biopsy confirmed pleuropulmonary blastoma (PPB) of type III. Despite receiving aggressive chemotherapy, the disease progressed rapidly and the outcome was fatal.This case highlights the diagnostic challenges of advanced PPB in adolescents and the poor prognosis once the disease metastasises. It also emphasises the importance of timely surgical management of CPAM and the need to consider screening in individuals with a family history of CPAM or DICER1 mutations.

Acute heart failure (AHF) is a major global health challenge, yet the relationship between New York Heart Association (NYHA) classification and objective markers such as echocardiography, lung ultrasound (LUS), and biomarkers remains unclear.

In this prospective two-center study, patients admitted with AHF (2022-2024) underwent echocardiography, 8-zone LUS, ECG, and biomarker sampling. Patients were stratified by NYHA class at enrollment, and associations with clinical, echocardiographic, and LUS measures were analyzed. Participants were invited for an identical follow-up examination 1-3 months post-discharge. The main outcome was a 180-day composite of AHF readmission or all-cause mortality evaluated across NYHA classes.

Among 564 patients (mean age 78.2 years; 56.3% male), 23% were classified as NYHA class I/II, 27% as NYHA class III, and 50% as NYHA class IV. Higher NYHA class at admission was associated with older age, greater comorbidity burden, lower left ventricular ejection fraction, impaired global longitudinal strain, higher E/e' ratio, and B-line count (all p <0.05). At follow-up (n = 160), left ventricular systolic function, B-line count, and left atrial size parameters were similar across baseline NYHA class. Atrial functional parameters (peak atrial longitudinal and contraction strain) remained lower with increasing NYHA class at admission (both p <0.05). NYHA class at admission was not associated with the 180-days outcome.

In this prospective study of hospitalized AHF patients, higher NYHA class at admission was associated with greater cardiac dysfunction, B-line burden, and comorbidity burden, but these differences largely resolved at follow-up. NYHA class at admission did not significantly predict the composite outcome.

Exercise-induced desaturation is a common symptom in chronic lung disease (CLD) and is associated with functional limitation and increased mortality. Although portable low-flow supplemental oxygen therapy (SOT) is commonly prescribed for exercise-induced hypoxaemia, evidence for SOT to improve performance is inconsistent.

This pragmatic, randomised, controlled, non-inferiority crossover trial enrolled patients with chronic obstructive pulmonary and interstitial lung disease who exhibited exercise-induced oxygen desaturation of >3%. Each patient performed two 6-minute walk distance (6MWD) tests in randomised order: one breathing ambient air and one using low-flow SOT delivered by a portable backpack concentrator (1-2 L/min). The primary outcome was 6MWD, secondary outcomes included perceived exertion and preference of the interventions. A predefined non-inferiority margin of 35 m was used.

Forty patients were enrolled (mean age 66±13 years; 14 women; 20 with chronic obstructive pulmonary disease (COPD), 20 with interstitial lung disease (ILD)). The mean difference in 6MWD between ambient air and SOT was 0 m (95% CI -14 to 13 m; p<0.001 for non-inferiority). Secondary outcomes demonstrated significantly lower dyspnoea scores with SOT both overall and within COPD/ILD subgroups. Patient preferences were split, with 49% favouring ambient air and 51% preferring SOT. A clinically meaningful improvement in 6MWD of >35 m was found in five patients.

In patients with CLD and exercise-induced desaturation, ambient air was non-inferior to pulsed low-dose SOT by portable concentrator in 6MWD, but SOT improved dyspnoea. These findings highlight the need for more effective, patient-acceptable oxygen delivery systems and further research to identify responders to SOT.

NCT06385301.

The healthcare community recognises the need for lower emission inhaler options; however, in the UK, most inhalers prescribed are pressurised metered dose inhalers (pMDIs) despite dry powder inhalers (DPIs) having a markedly lower carbon footprint as they do not contain propellants. For this reason, UK clinicians have been encouraged to offer switches from pMDIs to DPIs where feasible.

Using data from the Asthma+Lung UK's 'Life with a Lung Condition' 2023 online survey, demographic, economic and clinical factors were analysed to determine who had and had not been offered a switch; whose switch had been successful and why some respondents chose not to switch.

9960 people with asthma responded (77.9% female; age 59.9±13.0) and 7059 (87.7%) were pMDI users. The 3753 (53.2%) who were offered a pMDI to DPI switch had a greater awareness of lower-emission inhaler options (72% vs 53.2%*), uncontrolled asthma (61% vs 54.1%*), and had required unscheduled healthcare (27.4% vs 21.2%*) or >2 courses oral corticosteroids (27.6% vs 21.6%*) in the last year (all *p<0.001). 432 (11.5%) opted not to change inhaler when offered. 3321 (88.5%) accepted the switch and it was successful in 2126 (64%).

In a large UK survey of people with asthma, over half of those on pMDIs had been offered a switch. It was successful in most who attempted it but unsuccessful switches were associated with subjective and objective markers of poor disease control. Some patients decline the switch because they like their pMDI, but some have ongoing concerns about the efficacy and safety of a DPI and is most feasible when integrated into routine reviews for patients with stable disease, alongside ongoing efforts to optimise asthma outcomes.

A man in his 60s presented with diplopia, headache and facial numbness. Examination demonstrated a unilateral right abducens nerve palsy which rapidly progressed to a bilateral abducens palsy, partial right third nerve palsy and bilateral facial numbness. Nasendoscopy and imaging findings suggested an erosive fungal lesion centred on the sphenoid sinus. He underwent aggressive clearance with functional endoscopic sinus surgery, which revealed pan-sinus allergic fungal disease with marked bony erosion of the sphenoid, exposing the dura and optic chiasm. Corticosteroids and systemic antifungals were commenced postoperatively. Histopathology demonstrated eosinophilic mucin and no invasive features. However, no fungal organism was identified. His diplopia persisted for 8 weeks, resolving fully by twelve weeks. This case highlights chronic allergic fungal sinusitis as an important differential in patients with ocular complications, the diagnostic challenges which require multimodal assessment and MDT involvement, and the role of aggressive surgical management and postoperative corticosteroid and antifungal therapies.

The COVID-19 pandemic raised major concerns about its potential effects on children and adolescents, particularly through disruptions to their health, social and educational environments and the exacerbation of existing inequalities. In response to the limited evidence-based knowledge available at the time, the SEROCoV-KIDS study was launched in 2021 as a prospective cohort and biobank to assess the pandemic's effects on youth health and well-being. It focuses on the general population of Geneva, Switzerland, as well as subgroups with vulnerabilities, including prior SARS-CoV-2 infection, chronic health conditions and socioeconomic disadvantage.

A total of 2199 children and adolescents, aged 6 months to 17 years, from 1340 households were enrolled in the SEROCoV-KIDS cohort, 2048 from the general population and 151 from clinics (ie, children with chronic health conditions). At baseline, between December 2021 and June 2022, participants provided blood samples for serological testing and for long-term storage in the biobank, while comprehensive questionnaires were completed by a referent adult and adolescents aged 14 and older. Five follow-up online assessments were conducted until October 2026, addressing physical and mental health, development, quality of life, health behaviours, family dynamics and education-related topics. The quantitative findings of the cohort study were enriched by a cross-sectional qualitative study conducted between October 2023 and March 2024, focusing specifically on socioeconomically disadvantaged populations.

In the population-based sample, 66.3% of participants tested seropositive for anti-SARS-CoV-2 nucleocapsid antibodies at baseline, and 4.1% reported symptoms consistent with post-COVID-19 condition. Most children were minimally or not at all affected by the pandemic, showing good mental health over time. However, 8% of participants reported a positive pandemic impact, whereas 8%-13% experienced negative impacts, mainly due to disrupted routines and reduced social support. Health behaviours like physical activity and sleep remained largely stable over the study period. Higher screen time at baseline was associated with poorer well-being. Children with chronic health conditions or experiencing socioeconomic and family disadvantage were disproportionately affected in terms of the health and psychosocial consequences of the pandemic.

SEROCoV-KIDS demonstrates the value of child-focused cohorts for understanding the consequences of major societal events and for guiding evidence-based policy. Our next priority is to secure funding to prolong follow-up of this cohort and to maintain systematic surveillance of children and adolescents, so that emerging findings can directly inform public health and education policy over the coming years.

To understand the pre-admission factors associated with COVID-19 clinical outcome with and without controlling for acute COVID-19 severity score.

We ran a prospective, longitudinal, multicentre cohort study.

Patients were recruited from four hospitals and one community General Practice in England PARTICIPANTS: 425 patients with COVID-19 from the start of the UK pandemic in April 2020 through the first three waves with study completing in 2022.

Data were collected and analysed to identify demographic factors and preadmission symptoms for hospitalised patients that were associated with COVID-19 disease severity at recruitment, acute clinical course and long-term recovery. Analysis methods included logistic regression, time-to-event analysis, mixed-effect models and K-medoids clustering.

The cohort was skewed to patients with severe COVID (60%). Preadmission symptom cluster was associated with risk of thrombosis (OR 2.7 (95% CI 1.6 to 6.1), p=0.021) and renal disease (OR 3.3 (95% CI 1.4 to 8.0), p=0.008). Duration of symptoms less than 1 week was associated with pneumothorax (OR 3.1 (95% CI 1.2 to 8.3), p=0.025). Renal complications were more likely to be seen in the first wave compared with the second wave of the pandemic (OR 3.4 (95% CI 1.5 to 7.5), p=0.003). Using a logistic regression model, survival to discharge was associated with white (vs unknown) ethnicity (OR 6.6 (95% CI 2.8 to 15.2), p<0.0001), lower age (<40 years vs >60 years, OR 4.9 (95% CI 1.2 to 20.0), p=0.027) and absence of comorbidities (OR 2.7 (95% CI 1.2 to 5.9), p=0.016). However, using a survival model, hazard of death was increased for all hospitalised who had duration of symptoms less than 1 week (HR 5.6 (95% CI 1.3 to 24.4), p=0.023) or had comorbidities (HR 33.3 (95% CI 3.1 to 333.3), p=0.0035). Over 80% of patients reported long-term sequelae with neuromuscular and cognitive effects dominating early on and mood disturbance and breathlessness persisting to 12 months. Gender had the strongest association with dyspnoea (OR 99.8 (95% CI 2.4 to 4123.1, p=0.02) and persistent mood disorder (OR 8.3 (95% CI 1.7 to 39.9), p=0.008) and associated with persistent gastrointestinal problems (loose bowels (OR 3.3 (95% CI 1.1 to 10.8), p=0.045), abdominal pain (OR 5.0 (95% CI 1.4 to 18.1), p=0.014), constipation (OR 3.8 (95% CI 1.6 to 9.2), p=0.003)) and cognitive problems (OR 2.3 (95% CI 1.1 to -4.8), p=0.024).

These results support an association between specific demographic factors and early infection symptoms that impact on acute and long-term outcomes of COVID-19 in this cohort after accounting for COVID-19 disease severity at enrolment. Understanding the disease mechanisms that explain these relationships is needed to inform targeted therapeutics to prevent and/or manage these complications.