OBJECTIVE:The association between occupational exposure to chlorinated solvents and lung cancer remains inconclusive. This study investigated this relationship using data from the internationally pooled SYNERGY study. METHODS:Data from 14 case-control studies conducted in 13 European countries and Canada were pooled, including 28 048 participants (12 329 cases and 15 719 controls). Lifetime occupational exposure to chlorinated solvents was assessed using the ALOHA+job-exposure matrix. ORs and 95% CIs were estimated using unconditional logistic regression, adjusted for study centre, age, sex, smoking (pack-years and cessation), cumulative exposure to five occupational lung carcinogens (asbestos, hexavalent chromium, polycyclic aromatic hydrocarbons, respirable crystalline silica and diesel engine exhaust), cumulative benzene exposure and employment in high-risk occupations ('List A' jobs). Associations were estimated across categories of exposure levels, durations and analyses stratified by smoking status and lung cancer subtypes. RESULTS:We found no evidence of an association between ever exposure to chlorinated solvents and lung cancer risk (OR 1.03; 95% CI 0.96 to 1.10). Among exposed individuals, a positive trend with cumulative exposure was observed (p=0.031), but not when non-exposed individuals were included (p=0.173). Positive trends were found with exposure duration (p=0.005 for exposed; p=0.048 overall); risks were modestly elevated (OR 1.11) in those exposed for 20 or more years. No increased risk was observed across smoking strata or lung cancer subtypes. CONCLUSIONS:This pooled analysis provides limited evidence of an association between occupational exposure to chlorinated solvents and lung cancer, though exposure-response trends were noted among exposed individuals.

Supplementary Figure S16 shows proportions of (A) interchromosome and intrachromosome fusions and (B) fusions supported by structural variants (SV) across NS-LUAD expression subtypes. (C) Summary of types of genes involved in fusions. Circle sizes indicate the numbers of genes. D-E, (D) Numbers of protein-coding gene fusions per sample and (E) numbers of in-frame gene fusions per sample across NS-LUAD expression subtypes. Mean values are indicated by the yellow lines. P-values from two-sided Mann-Whitney U-test are shown.

Supplementary Table S5 shows gene signatures of hallmark genes and lung developmental pathways.

Most European Union (EU) residents live in areas where outdoor air pollution levels exceed the 2021 World Health Organization (WHO) air quality guidelines for fine particles and nitrogen dioxide. Outdoor air pollution is classified as carcinogenic to humans, and both outdoor and indoor air contain established human carcinogens, including diesel exhaust particulates, benzo(a)pyrene [B(A)P] and benzene. The European Code Against Cancer, 5th edition (ECAC5), incorporates recommendations for individuals and policymakers aimed at reducing the cancer burden from both outdoor and indoor air pollution. A critical step is aligning EU air quality limit values with the more stringent 2021 WHO guidelines. This should be complemented by integrated policy measures, including stricter regulation of combustion emissions, promotion of active and environmentally friendly transportation, incentives for cleaner energy sources for heating and cooking, and harmonization with broader EU climate initiatives. At the individual level, emissions and exposure may be reduced by limiting car use, avoiding second-hand smoke, and refraining from burning wood or coal indoors or outdoors. Further exposure reduction may be achieved by limiting walking or cycling along heavily trafficked routes.

Supplementary Figure S12 shows violin plots that depict signature genes for (A-B) fibroblasts (COL1A1, PDGFRA), (C) epithelial cells (EPCAM), (D-E) AT2 cells (SFTPB, SFTPC), (F-G) basal cells (KRT17, FHL2), (H-I) COL10A1+ and COL4A1+ cancer associated fibroblasts (COL10A1, COL4A1) and (J) non-malignant fibroblasts (VEGFD). Mean values are indicated by the yellow lines. P-values from two-sided Mann-Whitney U-test are shown.

Background Hemolytic uremic syndrome (HUS) related to Shiga toxin-producing Escherichia Coli (STEC) infection is a severe, life-threatening thrombotic microangiopathy (TMA). Endothelial damage causes platelet consumption and consequently platelet count is a key biomarker for monitoring disease activity. The present paper describes the time course of platelet count in a cohort of patients with STEC-HUS in order to provide references helpful in identifying subjects who divert from the expected course because complications. Methods All children treated at our Center with a well-established diagnosis of STEC-HUS during the period 2010–2025 were retrospectively enrolled and platelets count was recorded until discharge. The nadir of platelets count for each patient was used to align the results and investigate the time course towards platelets normalization. The cumulative percentage of platelets normalization was calculated on daily basis, together with the 10th centile of platelets count. Result During the 16 years under investigation, a total of 148 children were enrolled. The nadir of platelets count was 23,000/mm3 (IQR 14,000–39,000) on day 8 since the beginning of symptoms. By day 14 from the nadir, 100% of patients had reached a platelets count > 150.000/mm3. Conclusions Given that STEC-HUS is a self-limiting disease, the related TMA is expected to spontaneously cease within a defined time. If platelets count has a different course from the expected, the patient is likely to have complications that need to be actively searched for and treated accordingly (e.g. atypical HUS, disseminated intravascular coagulation or heparin induced thrombocytopenia).

BACKGROUND:Several studies have demonstrated the utility of urinary sediment (U-sed) examination in patients with glomerular diseases (GDs).In this prospective study we hypothesized that with a standardized approach for U-sed preparation and examination, we could distinguish proliferative GD (PGD) from non-proliferative GD (NPGD) and predict GD with a high activity score at renal biopsy (RB). METHODS:The U-sed of 285 patients with 12 different biopsy-proven GDs were investigated, 172 with PGD and 113 with NPGD. All RBs were scored for the presence/absence of active and chronic histologic lesions. For each U-sed we evaluated the frequency and number of red blood cells (RBCs), white blood cells (WBCs), renal tubular epithelial cells (RTECs) and 8 types of casts. We also compared the frequency and number of RBCs and WBCs with the results supplied by the reagent strips (R-strip) for urine haemoglobin (U-Hb) and leukocyte esterase (U-LE). RESULTS:Patients with PGD had higher frequencies and numbers of RBCs, WBCs, RTECs and of casts containing RBCs, WBCs and RTECs. PGD also had higher numbers of waxy casts while NPGD had higher numbers of fat casts. A good correlation was found between RBCs and U-Hb, while U-LE, compared with WBCs, supplied a high number of false negative results. In predicting PGD, U-sed RBCs and WBCs supplied the most significant area under the curve (AUC): 0.86 and 0.83, respectively; 0.88 when they were considered together versus 0.80 with combined U-Hb and U-LE. An expert U-sed examination adding RTEC and RBC casts, reached an AUC of 0.90. U-sed alone was also superior to the combination of patient's gender, age, serum creatinine and urine proteins (AUC = 0.84). When added to all these variables, U-sed reached an AUC of 0.96. CONCLUSION:U-sed is a useful tool to predict the presence of PGD with a high histological activity score.

Background Despite increasing concern over declining male reproductive health, epidemiological data remain limited, particularly in low- and middle-income countries. In Kazakhstan, updated information is scarce. This study analyzed national administrative data to describe temporal trends and regional differences in registered male infertility. Methods An ecological study was conducted using official administrative data on registered male infertility from 2020 to 2024. Data from 20 administrative units were analyzed. Average prevalence rates (per 100,000 males), temporal trends, and geographic distribution were assessed. Spearman correlation analysis evaluated associations between male infertility and healthcare resources. Results During 2020–2024, an average of 1,810 male infertility cases were registered annually, corresponding to a prevalence of 18.8 per 100,000 males. The highest prevalence rates were observed in Pavlodar, Astana, and Mangystau (93.3, 66.6, and 33.4 per 100,000, respectively), and the lowest in West Kazakhstan, Turkistan, and Akmola (2.1, 4.1, and 4.5). Marked regional heterogeneity was identified. Numbers of registered cases correlated with urologists and urological visits, whereas prevalence rates showed no significant association with either indicator. Conclusion Registered male infertility in Kazakhstan shows substantial regional variation. The findings suggest that differences in healthcare accessibility and reporting may contribute to the observed heterogeneity, warranting further investigation.

Supplementary Figure S9 shows violin plots that depict the LUAD histology scores across tumor stages in (A) all tumors and (B) within steady, proliferativeand chaotic subtypes, respectively. Mean values are indicated by the yellow lines. P-values from ordinal test are shown.

INTRODUCTION:Nitrous oxide, sevoflurane, and desflurane are hazardous chemicals used in surgery and dentistry to anaesthetise or sedate patients. During the use, they can be dispersed into the environment, causing exposure of healthcare workers. This study summarises 10 yrs of surveys in a large hospital in Milan, Italy. MATERIALS AND METHODS:Annual surveys were conducted from 2015 to 2024. Real-time monitoring and personal monitoring of exposure were performed. Biological monitoring was assessed by urinary nitrous oxide, desflurane, and hexafluoroisopropanol (metabolite of sevoflurane). RESULTS:101 surveys were performed in 25 operating theatres and 5 dentistry rooms, observing 219 interventions; 383 workers were investigated with 600 paired personal and biological measurements. Sevoflurane was the most used gas (49% alone, 5% with nitrous oxide), followed by nitrous oxide (7%) and desflurane (3% alone, 2% with nitrous oxide); no gas was used in 32% of cases. Median personal exposure for sevoflurane, nitrous oxide, and desflurane was <0.1, 1.4, and <0.1 ppm, with a 95th percentile of 1.2 ppm for sevoflurane in the anaesthesiologist and 428 ppm for nitrous oxide in the dentist. Median urinary hexafluoroisopropanol, nitrous oxide, and desflurane were <0.02 mg/L, <2 µg/L, and <0.3 µg/L, respectively. Real-time monitoring showed peaks of sevoflurane and desflurane during the refill of the vaporiser, the use of a facial mask for the induction, and the tracheal extubation; nitrous oxide peaks were observed during sedation in dentistry. Exposures were higher in paediatric than in adult surgery. CONCLUSION:Exposure to sevoflurane and desflurane in general anaesthesia is low; exposure to nitrous oxide in dentistry during sedation may overcome occupational limit values.

OBJECTIVES:Occupational factors affect SARS-CoV-2 infection risk, but the occupational factors associated with Long COVID (LC) are unknown. We aimed to address this issue using individual data in a population-based cohort. METHODS:In the prospective COVICAT study, 2020-2023, Catalonia, Spain, we examined the association between occupational determinants and LC. Among subjects with previous SARS-CoV-2 infection, those employed in the pandemic and with occupational information were analysed. Different metrics, including four job-exposure matrices, were used to evaluate individual occupational risk factors for LC (postinfection symptoms ≥3 months). Poisson models were used to estimate adjusted risk ratios (RRs) and 95% CIs. RESULTS:Among 2054 workers (1308 women, 746 men) aged 40-69 years, 486 developed LC (23.7%). Workers in jobs at high COVID-19 risk according to all metrics including health/social care, education, retail, transport and security showed higher LC risk. The main drivers of increased risk were close contact with colleagues and the public (RR up to 1.50; 95% CI 1.18 to 1.91), no social distance at workplace (up to 1.46; 95% CI 1.16 to 1.84), rare or no use of facemask (1.41; 95% CI 1.09 to 1.83) and commute by public transport (1.58; 95% CI 1.20 to 2.08). Working on-site during the pandemic was also associated with a higher LC risk compared with teleworking (1.57; 95% CI 1.19 to 2.09). Individual non-occupational risk factors for LC included female sex, comorbidities, obesity, number and severity of acute infections; vaccination and older age were protective. CONCLUSIONS:In a population-based cohort, several occupational factors increased LC risk. Focused preventive strategies are warranted to avoid the associated public health burden. LC should be recognised and compensated as an occupational disease.

Supplementary Table S4 shows NS-LUAD expression subtype-specific genes.

BACKGROUND:Approximately half of patients with chronic myeloid leukemia (CML) who attempted tyrosine kinase inhibitor (TKI) discontinuation for the first time experienced molecular relapse and restarted TKIs. Although several studies have already investigated first treatment-free remission (TFR) attempts (TFR1), few previously published articles have focused on the plausibility and predictors of second TFR (TFR2). METHODS:To evaluate the feasibility and likelihood of TFR2 success in real-life, 90 patients with CML regularly followed in 23 Italian hematological centers were analyzed; these patients reattempted TKI discontinuation after a first failed attempt. RESULTS:Forty-five (50.0%) patients lost major molecular response after a median of 4.0 months off therapy, whereas 45 (50.0%) remained treatment-free for a median of 18.8 months. In univariate analysis, there was no association between TFR2 and the following variables: age, gender, Sokal risk score, BCR::ABL1 transcript type, prior interferon exposure, type and number of previous TKIs, resistance to any prior TKIs, and TKI switching after TFR1. In contrast, factors identified as associated with TFR2 success included a lower ELTS risk score, a longer time from TFR1 to molecular relapse (≥3 months), as well as a longer TKI treatment and deep molecular response (DMR) duration (≥4 years) before TFR2. CONCLUSIONS:While confirming the critical prognostic role of ELTS risk and TKI treatment and DMR duration even before TFR2, this real-life study provides further information to support the safety of a second effort to discontinue TKIs in patients with CML, as a failed first attempt does not appear to preclude a second successful one.

Most solid tumors harbor somatic mutations attributed to off-target activities of APOBEC3A (A3A) and/or APOBEC3B (A3B). However, how APOBEC3A/B enzymes affect tumor evolution in the presence of exogenous mutagenic processes is largely unknown. Here, multi-omics profiling of 309 lung cancers from smokers identifies two subtypes defined by low (LAS) and high (HAS) APOBEC mutagenesis. LAS are enriched for A3B-like mutagenesis and KRAS mutations; HAS for A3A-like mutagenesis and TP53 mutations. Compared to LAS, HAS have older age at onset and high proportions of newly generated progenitor-like cells likely due to the combined tobacco smoking- and APOBEC3A-associated DNA damage and apoptosis. Consistently, HAS exhibit high expression of pulmonary healing signaling pathway, stemness markers, distal cell-of-origin, more neoantigens, slower clonal expansion, but no smoking-associated genomic/epigenomic changes. With validation in 184 lung tumor samples, these findings show how heterogeneity in mutational burden across co-occurring mutational processes and cell types contributes to tumor development.

Supplementary Figure from Occupational Exposure to Polycyclic Aromatic Hydrocarbons and Lung Cancer Risk: Results from a Pooled Analysis of Case–Control Studies (SYNERGY)

ABSTRACTIntroductionFetoscopic laser surgery (FLS) is the gold standard treatment for monochorionic (MC) twin pregnancies complicated by twin‐twin transfusion syndrome (TTTS). The aim of our study was to evaluate the rate and risk factors for cord entanglement in the presence of iatrogenic monoamnioticity (iMA), a consequence of inadvertent septostomy during FLS.MethodsThis is a retrospective analysis of two consecutive cohorts of FLS performed either using the selective technique from January 2004 to January 2012, or with the Solomon technique, from that date onwards. Maternal and fetal characteristics, technical details, and obstetrical and perinatal outcomes were recorded. Cord entanglement was identified based on the presence of a galloping sign observed during prenatal ultrasound in the presence of iMA. At our center, mono‐amniotic twins are electively delivered at 32 completed weeks.ResultsThe mean gestational age of the 558 FLS, 52.3% selective and 47.6% Solomon, was 19.8 weeks (15.1–26.4). Solomon laser coagulation was associated with a lower occurrence of TAPS or TTTS (5.3% vs. 13%, p = 0.001) after the FLS and a higher number of placental abruption (9% vs. 2% p < 0.001) and by more cord entanglement in the presence of iMA (9.4% vs. 2.4% respectively, p < 0.001). The presence of iMA was correlated with a higher occurrence of limb defects (6.2% vs. 1% in non‐iMA twins, p 0.001).ConclusionsSolomon FLS was associated with a higher risk of cord entanglement and placental abruptio. As a consequence, we delivered twins with iMA earlier.

Knowledge of tumor cell dynamics can inform prognosis and treatment yet is largely lacking for lung adenocarcinoma in people who have never smoked (NS-LUAD). With RNA-seq data from 684 NS-LUAD and validation in an independent dataset, we identified three subtypes with distinct phenotypic traits and cell compositions. Additional genomic and histological data further characterized the subtypes. 'Steady', marked by low proliferation, high alveolar cell fraction, moderate-to-well differentiation, and fewer driver genes' alterations, is linked to prolonged survival and low immune evasion. 'Proliferative' shows high proliferation markers, TP53 mutations, and gene fusions. 'Chaotic', with high epithelial-to-mesenchymal transition markers, has the worst prognosis even within stage I tumors. Lacking known molecular or histological characteristics, this aggressive subtype is solely identified by transcriptomic data. A 60-gene signature recapitulates the overall classification and strongly predicts survival even within subgroups based on tumor stage or known genomic features, emphasizing its potential for improving NS-LUAD prognostication in clinical settings.