Despite popular intuition, positive world beliefs poorly reflect several objective indicators of privilege, including wealth, health, sex, and neighborhood safety.

OBJECTIVES: We tested whether generalized beliefs that the world is safe, abundant, pleasurable, and progressing (termed "primal world beliefs") are associated with several objective measures of privilege. METHODS: Three studies (N = 16,547) tested multiple relationships between indicators of privilege-including socioeconomic status, health, sex, and neighborhood safety-and relevant world beliefs, as well as researchers and laypeople's expectations of these relationships. Samples were mostly from the USA and included general population samples (Study 2) as well as focused samples of academic researchers (Study 1) and people who had experienced serious illness or trauma (Study 3). RESULTS: Studies 1-2 found mostly negligible relationships between world beliefs and indicators of privilege, which were invariably lower than researcher predictions (e.g., instead of the expected r = 0.33, neighborhood affluence correlated with Abundant world belief at r = 0.01). Study 3 found that people who had experienced serious illness (cancer, cystic fibrosis) only showed modest differences in beliefs from controls. CONCLUSIONS: While results do not preclude that some individuals' beliefs were meaningfully affected by life events, they imply that such changes are smaller or less uniform than widely believed and that knowing a person's demographic background may tell us relatively little about their beliefs (and vice versa).

The usability of daytime and night-time heart rate dynamics as digital biomarkers of depression severity.

BACKGROUND: Alterations in heart rate (HR) may provide new information about physiological signatures of depression severity. This 2-year study in individuals with a history of recurrent major depressive disorder (MDD) explored the intra-individual variations in HR parameters and their relationship with depression severity. METHODS: Data from 510 participants (Number of observations of the HR parameters = 6666) were collected from three centres in the Netherlands, Spain, and the UK, as a part of the remote assessment of disease and relapse-MDD study. We analysed the relationship between depression severity, assessed every 2 weeks with the Patient Health Questionnaire-8, with HR parameters in the week before the assessment, such as HR features during all day, resting periods during the day and at night, and activity periods during the day evaluated with a wrist-worn Fitbit device. Linear mixed models were used with random intercepts for participants and countries. Covariates included in the models were age, sex, BMI, smoking and alcohol consumption, antidepressant use and co-morbidities with other medical health conditions. RESULTS: Decreases in HR variation during resting periods during the day were related with an increased severity of depression both in univariate and multivariate analyses. Mean HR during resting at night was higher in participants with more severe depressive symptoms. CONCLUSIONS: Our findings demonstrate that alterations in resting HR during all day and night are associated with depression severity. These findings may provide an early warning of worsening depression symptoms which could allow clinicians to take responsive treatment measures promptly.

Structure-based design of a SARS-CoV-2 Omicron-specific inhibitor.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) introduced a relatively large number of mutations, including three mutations in the highly conserved heptad repeat 1 (HR1) region of the spike glycoprotein (S) critical for its membrane fusion activity. We show that one of these mutations, N969K induces a substantial displacement in the structure of the heptad repeat 2 (HR2) backbone in the HR1HR2 postfusion bundle. Due to this mutation, fusion-entry peptide inhibitors based on the Wuhan strain sequence are less efficacious. Here, we report an Omicron-specific peptide inhibitor designed based on the structure of the Omicron HR1HR2 postfusion bundle. Specifically, we inserted an additional residue in HR2 near the Omicron HR1 K969 residue to better accommodate the N969K mutation and relieve the distortion in the structure of the HR1HR2 postfusion bundle it introduced. The designed inhibitor recovers the loss of inhibition activity of the original longHR2_42 peptide with the Wuhan strain sequence against the Omicron variant in both a cell-cell fusion assay and a vesicular stomatitis virus (VSV)-SARS-CoV-2 chimera infection assay, suggesting that a similar approach could be used to combat future variants. From a mechanistic perspective, our work suggests the interactions in the extended region of HR2 may mediate the initial landing of HR2 onto HR1 during the transition of the S protein from the prehairpin intermediate to the postfusion state.

Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy.

BACKGROUND: New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies. MATERIALS AND METHODS: A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts [treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO] were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers. RESULTS: TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (24%) tumours were manifest as an 'immune-desert' group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunotherapy trial datasets revealed that TMEHigh patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TMEHigh patients treated with adjuvant anti-PD-1 or oncolytic virus (PVSRIPO) showed a trend towards improved survival. CONCLUSIONS: We have established a novel TME-based classification system for application in intracranial malignancies. TME subtypes represent canonical 'termini a quo' (starting points) to support an improved precision immunotherapy treatment approach.

Nanomolar inhibition of SARS-CoV-2 infection by an unmodified peptide targeting the prehairpin intermediate of the spike protein.

Variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenge currently available coronavirus disease 2019 vaccines and monoclonal antibody therapies through epitope change on the receptor binding domain of the viral spike glycoprotein. Hence, there is a specific urgent need for alternative antivirals that target processes less likely to be affected by mutation, such as the membrane fusion step of viral entry into the host cell. One such antiviral class includes peptide inhibitors, which block formation of the so-called heptad repeat 1 and 2 (HR1HR2) six-helix bundle of the SARS-CoV-2 spike (S) protein and thus interfere with viral membrane fusion. We performed structural studies of the HR1HR2 bundle, revealing an extended, well-folded N-terminal region of HR2 that interacts with the HR1 triple helix. Based on this structure, we designed an extended HR2 peptide that achieves single-digit nanomolar inhibition of SARS-CoV-2 in cell-based and virus-based assays without the need for modifications such as lipidation or chemical stapling. The peptide also strongly inhibits all major SARS-CoV-2 variants to date. This extended peptide is ∼100-fold more potent than all previously published short, unmodified HR2 peptides, and it has a very long inhibition lifetime after washout in virus infection assays, suggesting that it targets a prehairpin intermediate of the SARS-CoV-2 S protein. Together, these results suggest that regions outside the HR2 helical region may offer new opportunities for potent peptide-derived therapeutics for SARS-CoV-2 and its variants, and even more distantly related viruses, and provide further support for the prehairpin intermediate of the S protein.

The AAA+ superfamily: a review of the structural and mechanistic principles of these molecular machines.

ATPases associated with diverse cellular activities (AAA+ proteins) are a superfamily of proteins found throughout all domains of life. The hallmark of this family is a conserved AAA+ domain responsible for a diverse range of cellular activities. Typically, AAA+ proteins transduce chemical energy from the hydrolysis of ATP into mechanical energy through conformational change, which can drive a variety of biological processes. AAA+ proteins operate in a variety of cellular contexts with diverse functions including disassembly of SNARE proteins, protein quality control, DNA replication, ribosome assembly, and viral replication. This breadth of function illustrates both the importance of AAA+ proteins in health and disease and emphasizes the importance of understanding conserved mechanisms of chemo-mechanical energy transduction. This review is divided into three major portions. First, the core AAA+ fold is presented. Next, the seven different clades of AAA+ proteins and structural details and reclassification pertaining to proteins in each clade are described. Finally, two well-known AAA+ proteins, NSF and its close relative p97, are reviewed in detail.

A nurse- and peer-led psycho-educational intervention to support women with gynaecological cancers receiving curative radiotherapy: The PeNTAGOn randomised controlled trial - ANZGOG 1102.

OBJECTIVE: Radiotherapy for gynaecological cancer is associated with multiple adverse effects. This randomised controlled trial evaluated the impact of a combined nurse- and peer-led psycho-educational intervention on psychological distress, preparation for treatment, quality of life, psychosexual function, unmet needs and vaginal stenosis. METHODS: Eligible women had a confirmed diagnosis of gynaecological cancer, scheduled to receive radiotherapy with curative intent, aged ≥18 years, and able to read and write English. Participants randomly assigned one-to-one to either four nurse-led consultations plus four peer-led telephone sessions, or to usual care. Participants completed study measures at baseline, immediately before first radiotherapy (FU1), and four weeks (FU2), three (FU3), six (FU4), and 12 months (FU5) post radiotherapy. The primary outcomes were psychological distress at FU1 and FU2 measured by the Hospital Anxiety and Depression Scale. RESULTS: Of 840 eligible participants, 625 were approached and 319 (51%) consented; 158 assigned to intervention, 160 to usual care with 1 withdrawing before randomisation. Between-groups differences for primary outcomes were trivial- and small-sized, (both p > 0.05). Notable effects on secondary outcomes favouring the intervention at FU2 included preparation for treatment (sensory/psychological concerns, d = 0.57; and procedural concerns, d = 0.52) and specific needs domains (sexuality needs, d = 0.38; and health system and information needs, d = 0.41). CONCLUSIONS: There was no evidence that a nurse- and peer-led intervention had a beneficial effect on psychological distress compared to usual care. However, improved treatment readiness and lower health system and sexuality needs indicate the intervention may have addressed outcomes known to be important to this population.

New hints towards a precision medicine strategy for IDH wild-type glioblastoma.

Glioblastoma represents the most common primary malignancy of the central nervous system in adults and remains a largely incurable disease. The elucidation of disease subtypes based on mutational profiling, gene expression and DNA methylation has so far failed to translate into improved clinical outcomes. However, new knowledge emerging from the subtyping effort in the IDH-wild-type setting may provide directions for future precision therapies. Here, we review recent learnings in the field, and further consider how tumour microenvironment differences across subtypes may reveal novel contexts of vulnerability. We discuss recent treatment approaches and ongoing trials in the IDH-wild-type glioblastoma setting, and propose an integrated discovery stratagem incorporating multi-omics, single-cell technologies and computational approaches.

Investigation of Novel RNA Elements in the 3'UTR of Tobacco Necrosis Virus-D.

RNA elements in the untranslated regions of plus-strand RNA viruses can control a variety of viral processes including translation, replication, packaging, and subgenomic mRNA production. The 3' untranslated region (3'UTR) of Tobacco necrosis virus strain D (TNV-D; genus Betanecrovirus, family Tombusviridae) contains several well studied regulatory RNA elements. Here, we explore a previously unexamined region of the viral 3'UTR, the sequence located upstream of the 3'-cap independent translation enhancer (3'CITE). Our results indicate that (i) a long-range RNA-RNA interaction between an internal RNA element and the 3'UTR facilitates translational readthrough, and may also promote viral RNA synthesis; (ii) a conserved RNA hairpin, SLX, is required for efficient genome accumulation; and (iii) an adenine-rich region upstream of the 3'CITE is dispensable, but can modulate genome accumulation. These findings identified novel regulatory RNA elements in the 3'UTR of the TNV-D genome that are important for virus survival.

Sarcopenia and myosteatosis in patients undergoing curative radiotherapy for head and neck cancer: Impact on survival, treatment completion, hospital admission and cost.

BACKGROUND: Computed tomography (CT) is the gold standard of body composition analysis at the tissue-organ level. The present study aimed to determine the impact of CT-defined sarcopenia and myosteatosis on outcomes, including overall survival, unplanned hospital admissions and related costs, in patients who had completed treatment of curative intent for head and neck cancer (HNC). METHODS: Retrospective observational study of patients undergoing radiotherapy of curative intent ± other treatment modalities for HNC. Tissue density data derived at the third lumbar vertebra (L3) were evaluated with sarcopenia defined per sex-specific published threshold values for skeletal muscle index, stratified by body mass index and mean skeletal muscle attenuation in HU (Hounsfield units). RESULTS: Pre- or post-treatment images were available for 79/98 patients (80.6%) and 61/98 patients (62.2%), respectively. Sarcopenia was present in 42/79 patients pre-treatment and 36/61 patients post-treatment, whereas myosteatosis was present in 63/79 patients pre-treatment and 48/61 patients post-treatment. In patients with pre- and post-treatment images (n = 60), the median (range) percentage weight change was -8.5% (-29.9 to +11.7). On multivariable analysis, a post-treatment sarcopenia hazard ratio of 3.87 (95% confidence interval = 1.22-12.24, P = 0.021) and a pre-treatment myosteatosis hazard ratio of 8.86 (95% confidence interval = 1.12-69.88, P = 0.038) were independent predictors of reduced overall survival. There was no difference in radiotherapy or chemotherapy treatment completion based on pre-treatment sarcopenia status. The mean (SD) difference unplanned hospital admission cost was $15 846 ($17 707) for patients without sarcopenia versus $47 945 ($82 688) for patients with sarcopenia at any time point (P = 0.077). CONCLUSIONS: As CT-defined sarcopenia and myosteatosis hold clinically meaningful prognostic value, muscle status evaluation is recommended in routine clinical practice.

Referral indications and prevalence of sleep abnormalities in children with early onset scoliosis.

This study describes the utility of overnight sleep studies in children with early onset scoliosis (EOS). Children with EOS have diminished respiratory reserve which is associated with abnormal breathing and sleep quality in children. Currently, there are no criteria for referral of these children to evaluate breathing during sleep or data on the use of sleep treatments as part of their supportive care. A review of the 159 patients with EOS who were followed at a single institution from 2003 to 2016 identified 68 who underwent overnight polysomnograms (PSGs). Sixty-five of 68 (96%) had elevated apnea-hypopnea index (AHI) and a majority (56%) were prescribed nighttime respiratory support. A majority of young children (< 5 years) with PSG were referred for a history of snoring, apnea, or restless sleep; all 30 had abnormal PSGs. Twenty-seven (90%) had nighttime hypoxemia (nadir oxygen saturation values < 92%). Eighteen (60%) were referred to otolaryngology, of whom 11 (37%) subsequently underwent tonsil and/or adenoid removal. In older children (≥ 5 years), those referred for PSGs had more severe restrictive chest wall disease [lower forced vital capacity (FVC) values] than those who were not sent for PSG. Correlation between FVC and apnea-hypopnea index, however, was not significant. Pre-operative coronal curve magnitude did not strongly correlate with nadir SaO2 or AHI in either age group. These results suggest that sleep studies are underutilized in the management of children with EOS. Inadequate and poor-quality sleep adversely affects growth, behavior, and cognitive function in children. This study suggests that screening for sleep abnormalities should be incorporated into assessment and treatment of more patients with EOS.

Systematic review of clinical practice guidelines for colorectal and anal cancer: the extent of recommendations for managing long-term symptoms and functional impairments.

PURPOSE: Due to increasing numbers of colorectal and anal cancer survivors, more individuals are living with long-term symptoms after treatment. A systematic review was undertaken to assess the extent to which practice guidelines for colorectal and anal cancer provide recommendations for managing long-term symptoms and functioning impairments. METHODS: Four electronic databases and websites of 30 international cancer societies were searched for clinical practice guidelines, consensus statements, or best practice recommendations for colorectal or anal cancer. Quality of included guidelines was evaluated with the Appraisal of Guidelines for Research & Evaluation II tool. Results were narratively summarized. RESULTS: We included 51 guidelines or consensus statements. Recommendations for managing long-term symptoms or functioning impairments were reported in 13 guidelines (25.4%). All 13 recommend a healthy lifestyle, diet, body weight, and physical activity. The ASCO Colorectal Cancer Survivorship Care Guideline is the most comprehensive, including interventions targeting sexual and bowel function to pain and cognitive issues, and also highlights limited evidence for informing management strategies. Other guidelines recommend treating incontinence, chronic diarrhea, and distress, and stress the need for greater awareness for sexual dysfunction, survivorship clinics, and referrals to specific supportive care interventions. CONCLUSIONS: Few clinical practice guidelines include recommendations for managing long-term symptoms and functioning impairments. It is unclear if this is due to limited evidence or absence of management strategies and interventions. Clear recommendations for managing long-term symptoms and functioning to help health professionals in supporting colorectal and anal cancer survivors are needed.

Close-kin mating, but not inbred parents, reduces hatching rates and offspring quality in a threatened tortoise.

Inbreeding depression, the reduction in fitness due to mating of related individuals, is of particular conservation concern in species with small, isolated populations. Although inbreeding depression is widespread in natural populations, long-lived species may be buffered from its effects during population declines due to long generation times and thus are less likely to have evolved mechanisms of inbreeding avoidance than species with shorter generation times. However, empirical evidence of the consequences of inbreeding in threatened, long-lived species is limited. In this study, we leverage a well-studied population of gopher tortoises, Gopherus polyphemus, to examine the role of inbreeding depression and the potential for behavioural inbreeding avoidance in a natural population of a long-lived species. We tested the hypothesis that increased parental inbreeding leads to reduced hatching rates and offspring quality. Additionally, we tested for evidence of inbreeding avoidance. We found that high parental relatedness results in offspring with lower quality and that high parental relatedness is correlated with reduced hatching success. However, we found that hatching success and offspring quality increase with maternal inbreeding, likely due to highly inbred females mating with more distantly related males. We did not find evidence for inbreeding avoidance in males and outbred females, suggesting sex-specific evolutionary trade-offs may have driven the evolution of mating behaviour. Our results demonstrate inbreeding depression in a long-lived species and that the evolution of inbreeding avoidance is shaped by multiple selective forces.

A 212-nt long RNA structure in the Tobacco necrosis virus-D RNA genome is resistant to Xrn degradation.

Plus-strand RNA viruses can accumulate viral RNA degradation products during infections. Some of these decay intermediates are generated by the cytosolic 5'-to-3' exoribonuclease Xrn1 (mammals and yeast) or Xrn4 (plants) and are formed when the enzyme stalls on substrate RNAs upon encountering inhibitory RNA structures. Many Xrn-generated RNAs correspond to 3'-terminal segments within the 3'-UTR of viral genomes and perform important functions during infections. Here we have investigated a 3'-terminal small viral RNA (svRNA) generated by Xrn during infections with Tobacco necrosis virus-D (family Tombusviridae). Our results indicate that (i) unlike known stalling RNA structures that are compact and modular, the TNV-D structure encompasses the entire 212 nt of the svRNA and is not functionally transposable, (ii) at least two tertiary interactions within the RNA structure are required for effective Xrn blocking and (iii) most of the svRNA generated in infections is derived from viral polymerase-generated subgenomic mRNA1. In vitro and in vivo analyses allowed for inferences on roles for the svRNA. Our findings provide a new and distinct addition to the growing list of Xrn-resistant viral RNAs and stalling structures found associated with different plant and animal RNA viruses.

Structural principles of SNARE complex recognition by the AAA+ protein NSF.

The recycling of SNARE proteins following complex formation and membrane fusion is an essential process in eukaryotic trafficking. A highly conserved AAA+ protein, NSF (N-ethylmaleimide sensitive factor) and an adaptor protein, SNAP (soluble NSF attachment protein), disassemble the SNARE complex. We report electron-cryomicroscopy structures of the complex of NSF, αSNAP, and the full-length soluble neuronal SNARE complex (composed of syntaxin-1A, synaptobrevin-2, SNAP-25A) in the presence of ATP under non-hydrolyzing conditions at ~3.9 Å resolution. These structures reveal electrostatic interactions by which two αSNAP molecules interface with a specific surface of the SNARE complex. This interaction positions the SNAREs such that the 15 N-terminal residues of SNAP-25A are loaded into the D1 ring pore of NSF via a spiral pattern of interactions between a conserved tyrosine NSF residue and SNAP-25A backbone atoms. This loading process likely precedes ATP hydrolysis. Subsequent ATP hydrolysis then drives complete disassembly.

Male Body Size Predicts Reproductive Success But Not Within-Clutch Paternity Patterns in Gopher Tortoises (Gopherus polyphemus).

In many vertebrates, body size is an important driver of variation in male reproductive success. Larger, more fit individuals are more likely to dominate mating opportunities, skewing siring success and resulting in lower effective population sizes and genetic diversity. The mating system of the gopher tortoise (Gopherus polyphemus) has been characterized as both female-defense and scramble-competition polygyny. Mating systems are typically not fixed and can be influenced by factors such as population density, demographic structure, and environmental conditions; however, most populations will have a predominant strategy that results from local conditions. We assessed how male body size influences patterns of paternity and reproductive success in a natural population of gopher tortoises in Florida, United States. Using microsatellites, we assigned parentage of 220 hatchlings from 31 nests collected during 2 reproductive seasons. Larger males were significantly more likely to sire offspring and sired more offspring than smaller males; however, the likelihood of a clutch being multiply sired was unrelated to male body size. We also found evidence of mate fidelity across years. Although paternity patterns in this high-density population are more consistent with defense polygyny, female monopoly by males was incomplete, with both large and small males contributing to multiply sired clutches. Additional behavioral data are needed to clarify the role of female mate selection in paternity outcomes. The context-dependence of mating systems underscores the need to compare parentage patterns across populations and to recognize the potential for more than 1 strategy to be employed within a single population.

Developmental considerations of young people with cancer transitioning to adulthood.

The literature concerning the impact of having cancer during adolescence and emerging adulthood has been widely discussed in relation to the unique nature of psychosocial challenges. The current study presents these findings within the context of developmental literature to further our understanding on how their developmental transitioning can be affected by having cancer. Specifically, two developmental milestones considered to be the pre-requisites for acquiring an adult status were focused on: forming identity and establishing independence. Several traditions of developmental literature were incorporated, including the psychosocial, sociological and psychoanalytical perspectives. The study discusses challenges to these developmental processes and suggests measures to foster young people's normative development.

Expression of T7-based constructs in tobacco cells.

Bacteriophage T7 promoter and RNA polymerase (T7-Pol) are widely used for recombinant protein expression in bacteria. In plants, there exists conflicting results regarding the efficacy of protein expression from T7-Pol-derived mRNAs. To reconcile these contradictory observations, the expression of green fluorescent protein (GFP) from T7 constructs was evaluated in tobacco protoplasts. T7 constructs transcribed by a nuclearly targeted T7-Pol did not express GFP in plant protoplasts, however T7-Pol lacking a nuclear targeting signal was able to translate cytosolically transcribed mRNAs, but only if the messages contained a viral translation enhancer. GFP expression was further evaluated at the plant level by using agroinfiltration-mediated transient expression system. Unlike for cytosolic expression, nuclear T7 transcripts containing a viral translation enhancer element did not express GFP, and modifications designed to stabilize and facilitate export of T7 transcripts to the cytosol did not improve the expression. We conclude that expression of nuclear T7 constructs is not feasible in tobacco cells, but cytosolic transcription provides an alternative means to over-express RNAs directly in the cytosol.

Evidence-practice gaps in lung cancer: A scoping review.

Lung cancer is a significant international health problem. Aligning clinical practice with evidence-based guideline recommendations has the potential to improve patient outcomes. This scoping review describes evidence-practice gaps across the diagnostic and management care pathway for lung cancer. We conducted searches of online databases Medline, PsychInfo, Cinahl and the Cochrane Library to identify studies published between 2008 and 2012. Of 614 articles screened, 65 met inclusion criteria. We identified seven evidence-practice gaps: (1) delays in timely diagnosis and referral; (2) curative and (3) palliative treatments are under-utilised; (4) older age and co-morbidities influence the use of treatments; (5) the benefits of multidisciplinary team review are not available to all lung cancer patients; (6) psychosocial needs are unmet; and (7) early referral to palliative care services is under-utilised. The scoping review highlighted three key messages: (1) there are significant challenges in the timely diagnosis and referral of lung cancer; (2) curative and palliative treatments, psychosocial support and palliative care are under-utilised in lung cancer management; and (3) variations in treatment utilisation appear to be associated with non-disease factors such as patient characteristics, provider practices and the organisation of health care services. Future research should focus on designing interventions to overcome variations in care.