Physical Health and Transition to Psychosis in People at Clinical High Risk.

BACKGROUND: The clinical high risk for psychosis (CHR-P) construct represents an opportunity for prevention and early intervention in young adults, but the relationship between risk for psychosis and physical health in these patients remains unclear. METHODS: We conducted a RECORD-compliant clinical register-based cohort study, selecting the long-term cumulative risk of developing a persistent psychotic disorder as the primary outcome. We investigated associations between primary outcome and physical health data with Electronic Health Records at the South London and Maudsley (SLaM) NHS Trust, UK (January 2013-October 2020). We performed survival analyses using Kaplan-Meier curves, log-rank tests, and Cox proportional hazard models. RESULTS: The database included 137 CHR-P subjects; 21 CHR-P developed psychosis during follow-up, and the cumulative incidence of psychosis risk was 4.9% at 1 year and 56.3% at 7 years. Log-rank tests suggested that psychosis risk might change between different levels of nicotine and alcohol dependence. Kaplan-Meier curve analyses indicated that non-hazardous drinkers may have a lower psychosis risk than non-drinkers. In the Cox proportional hazard model, nicotine dependence presented a hazard ratio of 1.34 (95% CI: 1.1-1.64) (p = 0.01), indicating a 34% increase in psychosis risk for every additional point on the Fagerström Test for Nicotine Dependence. CONCLUSIONS: Our findings suggest that a comprehensive assessment of tobacco and alcohol use, diet, and physical activity in CHR-P subjects is key to understanding how physical health contributes to psychosis risk.

Magnetically controlled cyclic microscale deformation of in vitro cancer invasion models.

Mechanical cues play an important role in the metastatic cascade of cancer. Three-dimensional (3D) tissue matrices with tunable stiffness have been extensively used as model systems of the tumor microenvironment for physiologically relevant studies. Tumor-associated cells actively deform these matrices, providing mechanical cues to other cancer cells residing in the tissue. Mimicking such dynamic deformation in the surrounding tumor matrix may help clarify the effect of local strain on cancer cell invasion. Remotely controlled microscale magnetic actuation of such 3D in vitro systems is a promising approach, offering a non-invasive means for in situ interrogation. Here, we investigate the influence of cyclic deformation on tumor spheroids embedded in matrices, continuously exerted for days by cell-sized anisotropic magnetic probes, referred to as µRods. Particle velocimetry analysis revealed the spatial extent of matrix deformation produced in response to a magnetic field, which was found to be on the order of 200 µm, resembling strain fields reported to originate from contracting cells. Intracellular calcium influx was observed in response to cyclic actuation, as well as an influence on cancer cell invasion from 3D spheroids, as compared to unactuated controls. Furthermore, RNA sequencing revealed subtle upregulation of certain genes associated with migration and stress, such as induced through mechanical deformation, for spheroids exposed to actuation vs. controls. Localized actuation at one side of a tumor spheroid tended to result in anisotropic invasion toward the µRods causing the deformation. In summary, our approach offers a strategy to test and control the influence of non-invasive micromechanical cues on cancer cell invasion and metastasis.

Parsing neurobiological heterogeneity of the clinical high-risk state for psychosis: A pseudo-continuous arterial spin labelling study.

Introduction: The impact of the clinical high-risk for psychosis (CHR-P) construct is dependent on accurately predicting outcomes. Individuals with brief limited intermittent psychotic symptoms (BLIPS) have higher risk of developing a first episode of psychosis (FEP) compared to individuals with attenuated psychotic symptoms (APS). Supplementing subgroup stratification with information from candidate biomarkers based on neurobiological parameters, such as resting-state, regional cerebral blood flow (rCBF), may help refine risk estimates. Based on previous evidence, we hypothesized that individuals with BLIPS would exhibit increased rCBF compared to APS in key regions linked to dopaminergic pathways. Methods: Data from four studies were combined using ComBat (to account for between-study differences) to analyse rCBF in 150 age- and sex-matched subjects (n = 30 healthy controls [HCs], n = 80 APS, n = 20 BLIPS and n = 20 FEP). Global gray matter (GM) rCBF was examined in addition to region-of-interest (ROI) analyses in bilateral/left/right frontal cortex, hippocampus and striatum. Group differences were assessed using general linear models: (i) alone; (ii) with global GM rCBF as a covariate; (iii) with global GM rCBF and smoking status as covariates. Significance was set at p < 0.05. Results: Whole-brain voxel-wise analyses and Bayesian ROI analyses were also conducted. No significant group differences were found in global [F(3,143) = 1,41, p = 0.24], bilateral frontal cortex [F(3,143) = 1.01, p = 0.39], hippocampus [F(3,143) = 0.63, p = 0.60] or striatum [F(3,143) = 0.52, p = 0.57] rCBF. Similar null findings were observed in lateralized ROIs (p > 0.05). All results were robust to addition of covariates (p > 0.05). No significant clusters were identified in whole-brain voxel-wise analyses (p > 0.05FWE). Weak-to-moderate evidence was found for an absence of rCBF differences between APS and BLIPS in Bayesian ROI analyses. Conclusion: On this evidence, APS and BLIPS are unlikely to be neurobiologically distinct. Due to this and the weak-to-moderate evidence for the null hypothesis, future research should investigate larger samples of APS and BLIPS through collaboration across large-scale international consortia.

Prevalence of tobacco smoking in people at clinical high-risk for psychosis: Systematic review and meta-analysis.

Several hypotheses have been proposed to explain why individuals with psychosis consume more tobacco compared with the general population, but the reasons remain unclear. The phases predating the onset of psychosis could provide an interesting framework to clarify this association. The aim of this systematic review and meta-analysis is to provide an updated and comprehensive synthesis of the association between tobacco smoking and Clinical High Risk for Psychosis (CHRP) status. We performed a multistep systematic PRISMA/MOOSE-compliant electronic search for articles published from inception until October 1st, 2021. Web of Science was searched, complemented by a manual search of original articles reporting the outcome of tobacco consumption (defined as the number of individuals which were smoking tobacco at baseline) in a group of CHR-P patients versus healthy controls (HC). We employed quality assessment of the included studies with Newcastle Ottawa Scale (NOS). The effect size for the primary outcome was the odds ratio (OR) of smoking tobacco in CHR-P samples vs HC. We performed a random-effects model meta-analysis, assessment of heterogeneity with I2 index, sensitivity analyses excluding one study at a time for primary outcome, meta-regressions with four independent moderators (mean age, female ratio, sample size, NOS) and assessment of publication bias with funnel plot and Egger's test. We included 21 independent articles, totalling 2018 CHR-P individuals (mean age of 21.35 ± 2.91 years and average female ratio of 41 ± 7 %) and 1160 HC (mean age of 22.42 ± 3.70 years and average female ratio of 45 ± 11 %). The NOS score was 6.52 ± 1.25 (range from 0 to 9). The OR of smoking status was 2.22 (95%CI 1.74-2.84, p < 0.01). Heterogeneity (I2) was 24.09 (p = 0.16). Sensitivity analyses, removing one study at a time, revealed the robustness of our main finding. Meta-regressions did not reveal any significant association between the moderators and the main outcome. Visual inspection of the funnel plot and Egger's test did not reveal evident publication bias. Our main finding of an increased OR of smokers in the CHR-P individuals compared to healthy controls corroborates the accumulation of unhealthy lifestyles in this vulnerable group. This does not demonstrate any causal association between tobacco smoking and incidence of psychosis, which should be investigated in future prospective cohorts. In conclusion, the window of opportunity represented by CHR-P status should involve more efficient physical health screening and better investigating the aetiological impact of smoking in the development of psychosis.

Single-cell profiling of alveolar rhabdomyosarcoma reveals RAS pathway inhibitors as cell-fate hijackers with therapeutic relevance.

Rhabdomyosarcoma (RMS) is a group of pediatric cancers with features of developing skeletal muscle. The cellular hierarchy and mechanisms leading to developmental arrest remain elusive. Here, we combined single-cell RNA sequencing, mass cytometry, and high-content imaging to resolve intratumoral heterogeneity of patient-derived primary RMS cultures. We show that the aggressive alveolar RMS (aRMS) subtype contains plastic muscle stem-like cells and cycling progenitors that drive tumor growth, and a subpopulation of differentiated cells that lost its proliferative potential and correlates with better outcomes. While chemotherapy eliminates cycling progenitors, it enriches aRMS for muscle stem-like cells. We screened for drugs hijacking aRMS toward clinically favorable subpopulations and identified a combination of RAF and MEK inhibitors that potently induces myogenic differentiation and inhibits tumor growth. Overall, our work provides insights into the developmental states underlying aRMS aggressiveness, chemoresistance, and progression and identifies the RAS pathway as a promising therapeutic target.

Physical Health in Clinical High Risk for Psychosis Individuals: A Cross-Sectional Study.

BACKGROUND: The clinical high risk for psychosis (CHR-P) phase represents an opportunity for prevention and early intervention in young adults, which also could focus on improving physical health trajectories. METHODS: We conducted a RECORD-compliant clinical register-based cohort study. The primary outcome was to describe the physical health of assessed CHR-P individuals, obtained via Electronic Health Records at the South London and Maudsley (SLaM) NHS Foundation Trust, UK (January 2013-October 2020). RESULTS: The final database included 194 CHR-P subjects (46% female). Mean age was 23.70 ± 5.12 years. Percentage of tobacco smokers was 41% (significantly higher than in the age-matched general population [24%]). We found that 49% of subjects who consumed alcohol had an AUDIT-C (Alcohol Use Disorder Identification Test) score above 5 (hazardous drinking), with an average score of 4.94 (significantly higher than in the general population [2.75]). Investigating diet revealed low fiber intake in most subjects and high saturated fat intake in 10% of the individuals. We found that 47% of CHR-P subjects met the UK recommended physical activity guidelines (significantly lower than in the general population [66%]). Physical parameters (e.g., weight, heart rate, blood pressure) were not significantly different from the general population. CONCLUSIONS: This evidence corroborates the need for monitoring physical health parameters in CHR-P subjects, to implement tailored interventions that target daily habits.

Quantum Dot-Based Screening Identifies F3 Peptide and Reveals Cell Surface Nucleolin as a Therapeutic Target for Rhabdomyosarcoma.

Active drug delivery by tumor-targeting peptides is a promising approach to improve existing therapies for rhabdomyosarcoma (RMS), by increasing the therapeutic effect and decreasing the systemic toxicity, e.g., by drug-loaded peptide-targeted nanoparticles. Here, we tested 20 different tumor-targeting peptides for their ability to bind to two RMS cell lines, Rh30 and RD, using quantum dots Streptavidin and biotin-peptides conjugates as a model for nanoparticles. Four peptides revealed a very strong binding to RMS cells: NCAM-1-targeting NTP peptide, nucleolin-targeting F3 peptide, and two Furin-targeting peptides, TmR and shTmR. F3 peptide showed the strongest binding to all RMS cell lines tested, low binding to normal control myoblasts and fibroblasts, and efficient internalization into RMS cells demonstrated by the cytoplasmic delivery of the Saporin toxin. The expression of the nucleophosphoprotein nucleolin, the target of F3, on the surface of RMS cell lines was validated by competition with the natural ligand lactoferrin, by colocalization with the nucleolin-binding aptamer AS1411, and by the marked sensitivity of RMS cell lines to the growth inhibitory nucleolin-binding N6L pseudopeptide. Taken together, our results indicate that nucleolin-targeting by F3 peptide represents a potential therapeutic approach for RMS.

Response and resistance to BRAFV600E inhibition in gliomas: Roadblocks ahead?

BRAFV600E represents the most common BRAF mutation in all human cancers. Among central nervous system (CNS) tumors, BRAFV600E is mostly found in pediatric low-grade gliomas (pLGG, ~20%) and, less frequently, in pediatric high-grade gliomas (pHGG, 5-15%) and adult glioblastomas (GBM, ~5%). The integration of BRAF inhibitors (BRAFi) in the treatment of patients with gliomas brought a paradigm shift to clinical care. However, not all patients benefit from treatment due to intrinsic or acquired resistance to BRAF inhibition. Defining predictors of response, as well as developing strategies to prevent resistance to BRAFi and overcome post-BRAFi tumor progression/rebound growth are some of the main challenges at present in the field. In this review, we outline current achievements and limitations of BRAF inhibition in gliomas, with a special focus on potential mechanisms of resistance. We discuss future directions of targeted therapy for BRAFV600E mutated gliomas, highlighting how insights into resistance to BRAFi could be leveraged to improve outcomes.

Universal and Selective Interventions to Prevent Poor Mental Health Outcomes in Young People: Systematic Review and Meta-analysis.

BACKGROUND: Much is not known about the efficacy of interventions to prevent poor mental health outcomes in young people by targeting either the general population (universal prevention) or asymptomatic individuals with high risk of developing a mental disorder (selective prevention). METHODS: We conducted a PRISMA/MOOSE-compliant systematic review and meta-analysis of Web of Science to identify studies comparing post-test efficacy (effect size [ES]; Hedges' g) of universal or selective interventions for poor mental health outcomes versus control groups, in samples with mean age <35 years (PROSPERO: CRD42018102143). Measurements included random-effects models, I2 statistics, publication bias, meta-regression, sensitivity analyses, quality assessments, number needed to treat, and population impact number. RESULTS: 295 articles (447,206 individuals; mean age = 15.4) appraising 17 poor mental health outcomes were included. Compared to control conditions, universal and selective interventions improved (in descending magnitude order) interpersonal violence, general psychological distress, alcohol use, anxiety features, affective symptoms, other emotional and behavioral problems, consequences of alcohol use, posttraumatic stress disorder features, conduct problems, tobacco use, externalizing behaviors, attention-deficit/hyperactivity disorder features, and cannabis use, but not eating-related problems, impaired functioning, internalizing behavior, or sleep-related problems. Psychoeducation had the highest effect size for ADHD features, affective symptoms, and interpersonal violence. Psychotherapy had the highest effect size for anxiety features. CONCLUSION: Universal and selective preventive interventions for young individuals are feasible and can improve poor mental health outcomes.

Cells expressing PAX8 are the main source of homeostatic regeneration of adult mouse endometrial epithelium and give rise to serous endometrial carcinoma.

Humans and mice have cyclical regeneration of the endometrial epithelium. It is expected that such regeneration is ensured by tissue stem cells, but their location and hierarchy remain debatable. A number of recent studies have suggested the presence of stem cells in the mouse endometrial epithelium. At the same time, it has been reported that this tissue can be regenerated by stem cells of stromal/mesenchymal or bone marrow cell origin. Here, we describe a single-cell transcriptomic atlas of the main cell types of the mouse uterus and epithelial subset transcriptome and evaluate the contribution of epithelial cells expressing the transcription factor PAX8 to the homeostatic regeneration and malignant transformation of adult endometrial epithelium. According to lineage tracing, PAX8+ epithelial cells are responsible for long-term maintenance of both luminal and glandular epithelium. Furthermore, multicolor tracing shows that individual glands and contiguous areas of luminal epithelium are formed by clonal cell expansion. Inactivation of the tumor suppressor genes Trp53 and Rb1 in PAX8+ cells, but not in FOXJ1+ cells, leads to the formation of neoplasms with features of serous endometrial carcinoma, one of the most aggressive types of human endometrial malignancies. Taken together, our results show that the progeny of single PAX8+ cells represents the main source of regeneration of the adult endometrial epithelium. They also provide direct experimental genetic evidence for the key roles of the P53 and RB pathways in the pathogenesis of serous endometrial carcinoma and suggest that PAX8+ cells represent the cell of origin of this neoplasm.

Musculoskeletal Consequences of COVID-19.

Coronavirus disease 2019 (COVID-19) is an emerging pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although the majority of patients who become infected with SARS-CoV-2 are asymptomatic or have mild symptoms, some patients develop severe symptoms that can permanently detract from their quality of life. SARS-CoV-2 is closely related to SARS-CoV-1, which causes severe acute respiratory syndrome (SARS). Both viruses infect the respiratory system, and there are direct and indirect effects of this infection on multiple organ systems, including the musculoskeletal system. Epidemiological data from the SARS pandemic of 2002 to 2004 identified myalgias, muscle dysfunction, osteoporosis, and osteonecrosis as common sequelae in patients with moderate and severe forms of this disease. Early studies have indicated that there is also considerable musculoskeletal dysfunction in some patients with COVID-19, although long-term follow-up studies have not yet been conducted. The purpose of this article was to summarize the known musculoskeletal pathologies in patients with SARS or COVID-19 and to combine this with computational modeling and biochemical signaling studies to predict musculoskeletal cellular targets and long-term consequences of the SARS-CoV-2 infection.

A reference single-cell transcriptomic atlas of human skeletal muscle tissue reveals bifurcated muscle stem cell populations.

Single-cell RNA-sequencing (scRNA-seq) facilitates the unbiased reconstruction of multicellular tissue systems in health and disease. Here, we present a curated scRNA-seq dataset of human muscle samples from 10 adult donors with diverse anatomical locations. We integrated ~ 22,000 single-cell transcriptomes using Scanorama to account for technical and biological variation and resolved 16 distinct populations of muscle-resident cells using unsupervised clustering of the data compendium. These cell populations included muscle stem/progenitor cells (MuSCs), which bifurcated into discrete "quiescent" and "early-activated" MuSC subpopulations. Differential expression analysis identified transcriptional profiles altered in the activated MuSCs including genes associated with aging, obesity, diabetes, and impaired muscle regeneration, as well as long non-coding RNAs previously undescribed in human myogenic cells. Further, we modeled ligand-receptor cell-communication interactions and observed enrichment of the TWEAK-FN14 pathway in activated MuSCs, a characteristic signature of muscle wasting diseases. In contrast, the quiescent MuSCs have enhanced expression of the EGFR receptor, a recognized human MuSC marker. This work provides a new benchmark reference resource to examine human muscle tissue heterogeneity and identify potential targets in MuSC diversity and dysregulation in disease contexts.

Transcatheter aortic valve replacement in the setting of left atrial appendage thrombus.

OBJECTIVES: Left atrial appendage thrombus (LAT) was an exclusion criterion in the seminal transcatheter aortic valve replacement (TAVR) trials; however, such patients do undergo TAVR in the 'real-world' setting. This study sought to analyse outcomes after TAVR in patients with LAT or spontaneous echo contrast (SEC). METHODS: All patients undergoing TAVR at our institution between March 2009 and December 2014 were prospectively analysed. The presence of LAT or SEC was determined via a retrospective chart review. Primary outcomes included 30-day and 1-year neurological events as well as mortality. RESULTS: Of the 369 patients undergoing TAVR, 3.8% (14) were found to have LAT and 6.8% (25) were found to have SEC, and they were separately compared to patients who did not have LAT or SEC. Significant differences were noted between groups with regard to preoperative renal function, atrial fibrillation and ejection fraction. Preoperative atrial fibrillation was the only independent predictor of LAT. No perioperative complications were associated with the presence of LAT or SEC. Specifically, no patient with LAT or SEC experienced a postoperative neurological event. While neither LAT nor SEC was an independent predictor of 30-day mortality, LAT was an independent predictor of 1-year mortality (odds ratio 3.573, 95% confidence interval 1.040-12.28; P = 0.042). CONCLUSIONS: The current study suggests that TAVR may be performed in patients with LAT and SEC with a low risk of embolic complications. While neither was an independent predictor of 30-day mortality, LAT was an independent predictor of 1-year mortality. Larger studies are needed to better study this phenomenon.

[Excess deaths for haematological tumours in Falconara Marittima (Marche Region, Central Italy): short story from the epidemiological survey up to now]. / EPICHANGE/3. Eccesso di morti per tumori ematologici a Falconara Marittima: breve storia dall'indagine epidemiologica a oggi.

API is a company refining petroleum products located in Falconara Marittima (Ancona Province, Marche Region, Central Italy). Thanks to the pressure made by citizens' committees, which considered the plant as a risk source for the population residing in the surroundings municipalities, Marche Region as institution asked for an epidemiological survey. This survey found a significative excess in deaths for haematological tumours in women and in a sub-group of retired and elderly. The results were published in one report and two scientific journals, and were also presented during a public meeting. It was urgent to made public health intervention, which were called for, but up to now nothing has been done. Here, the reconstruction of this affair, from the start of the epidemiological survey up to the more recent development in terms of public health.

Out-of-pocket costs for cancer survivors between 5 and 10 years from diagnosis: an Italian population-based study.

PURPOSE: To illustrate the out-of-pocket (OOP) costs incurred by a population-based group of patients from 5 to 10 years since their cancer diagnosis in a country with a nationwide public health system. METHODS: Interviews on OOP costs to a sample of 5-10 year prevalent cases randomly extracted from four population-based cancer registries (CRs), two in the north and two in the south of Italy. The patients' general practitioners (GPs) gave assurance about the patient's physical and psychological condition for the interview. A zero-inflated negative binomial model was used to analyze OOP cost determinants. RESULTS: Two hundred six cancer patients were interviewed (48 % of the original sample). On average, a patient in the north spent €69 monthly, against €244 in the south. The main differences are for transport, room, and board (TRB) to reach the hospital and/or the cancer specialist (north €0; south €119). Everywhere, OOP costs without TRB costs were higher for patients with a low quality of life. CONCLUSIONS: Despite the limited participation, our study sample's characteristics are similar to those of the Italian cancer prevalence population, allowing us to generalize the results. The higher OOP costs in the south may be due to the scarcity of oncologic structures, obliging patients to seek assistance far from their residence. Implications for cancer survivors Cancer survivors need descriptive studies to show realistic data about their status. Future Italian and European descriptive studies on cancer survivorship should be based on population CRs and involve GPs in order to approach the patient at best.

Age and case mix-standardised survival for all cancer patients in Europe 1999-2007: Results of EUROCARE-5, a population-based study.

BACKGROUND: Overall survival after cancer is frequently used when assessing a health care service's performance as a whole. It is mainly used by the public, politicians and the media, and is often dismissed by clinicians because of the heterogeneous mix of different cancers, risk factors and treatment modalities. Here we give survival details for all cancers combined in Europe, correlating it with economic variables to suggest reasons for differences. METHODS: We computed age and cancer site case-mix standardised relative survival for all cancers combined (ACRS) for 29 countries participating in the EUROCARE-5 project with data on more than 7.5million cancer cases from 87 population-based cancer registries, using complete and period approach. RESULTS: Denmark, United Kingdom (UK) and Eastern European countries had lower survival than neighbouring countries. Five-year ACRS has been increasing throughout Europe, and substantial increases, between 1999-2001 and 2005-2007, have been achieved in countries where survival was lower in the past. Five-year ACRS for men and women are positively correlated with macro-economic variables like the Gross Domestic Product (GDP) and Total National Expenditure on Health (TNEH) (R2 about 70%). Countries with recent larger increases in GDP and TNEH had greater increases in cancer survival. CONCLUSIONS: ACRS serves to compare all cancer survival in Europe taking account of the geographical variability in case-mixes. The EUROCARE-5 data on ACRS confirm previous EUROCARE findings. Survival appears to correlate with macro-economic determinants, particularly with investments in the health care system.

Spatial variation in mortality risk for hematological malignancies near a petrochemical refinery: A population-based case-control study.

INTRODUCTION: The study investigated the geographic variation of mortality risk for hematological malignancies (HMs) in order to identify potential high-risk areas near an Italian petrochemical refinery. MATERIAL AND METHODS: A population-based case-control study was conducted and residential histories for 171 cases and 338 sex- and age-matched controls were collected. Confounding factors were obtained from interviews with consenting relatives for 109 HM deaths and 267 controls. To produce risk mortality maps, two different approaches were applied and compared. We mapped (1) adaptive kernel density relative risk estimation for case-control studies which estimates a spatial relative risk function using the ratio between cases and controls' densities, and (2) estimated odds ratios for case-control study data using Generalized Additive Models (GAMs) to smooth the effect of location, a proxy for exposure, while adjusting for confounding variables. RESULTS: No high-risk areas for HM mortality were identified among all subjects (men and women combined), by applying both approaches. Using the adaptive KDE approach, we found a significant increase in death risk only among women in a large area 2-6 km southeast of the refinery and the application of GAMs also identified a similarly-located significant high-risk area among women only (global p-value<0.025). Potential confounding risk factors we considered in the GAM did not alter the results. CONCLUSION: Both approaches identified a high-risk area close to the refinery among women only. Those spatial methods are useful tools for public policy management to determine priority areas for intervention. Our findings suggest several directions for further research in order to identify other potential environmental exposures that may be assessed in forthcoming studies based on detailed exposure modeling.

Risk of death for hematological malignancies for residents close to an Italian petrochemical refinery: a population-based case-control study.

PURPOSE: We investigated the risk of death for hematological malignancies (HMs) in the area surrounding an Italian petrochemical refinery, where atmospheric concentrations of benzene (known carcinogen) had not been adequately monitored in the past. METHODS: We performed a population-based case-control study, using conditional logistic regression to estimate odds ratios (ORs) of HM death, with 95 % confidence intervals (CIs), and p trends, in relation to tertiles of time-weighted average residential proximity to the refinery. We identified 177 HM deaths and 349 sex- and age-matched controls from municipal files. Confounding factors were investigated from interviews with consenting relatives for 109 HM deaths and 178 matched controls. RESULTS: For males and females combined, risk of HM death was unrelated to residential proximity. For females, ORs of HM death by increasing tertiles of proximity were 1, 2.74 (95 % CI 1.48-5.09, significant) and 1.49 (95 % CI 0.76-2.92) (p trend 0.184). For the subgroup of persons who plausibly spent most of their time at home (long-term retired, homemakers or unemployed, 53 cases, 79 controls), the ORs of leukemia plus non-Hodgkin lymphoma death (38 cases, 56 controls) by increasing tertiles of proximity were 1, 3.44 (95 % CI 1.04-11.37, significant) and 3.25 (95 % CI 0.82-12.87) (p trend 0.083). CONCLUSIONS: No increased risk of HM death for males and females combined living close to the refinery was found. However, the findings for females and a subgroup plausibly spending most of their time at home suggest a relation between increased risk of HM death and residential proximity to the refinery.