Faltering mortality improvements at young-middle ages in high-income English-speaking countries.

BACKGROUND: Before the COVID-19 pandemic, stagnating life expectancy trends were reported in some high-income countries (HICs). Despite previous evidence from country-specific studies, there is a lack of comparative research that provides a broader perspective and challenges existing assumptions. This study aims to examine longevity trends and patterns in six English-speaking countries (Australia, Canada, Ireland, New Zealand, United Kingdom, United States) by combining period and cohort perspectives and to compare them with other HICs. METHODS: Using data from the Human Mortality and World Health Organization Mortality Databases, we estimated partial life expectancy, lifespan inequality and cohort survival differences for 1970-2021, as well as the contribution of causes of death to the gap in life expectancy between English-speaking countries and the average for other HICs in 2017-19. RESULTS: In the pre-pandemic period, the increase in life expectancy slowed in all English-speaking countries, except Ireland, mainly due to stagnating or rising mortality at young-middle ages. Relative to other HICs, those born in Anglophone countries since the 1970s experienced relative survival disadvantage, largely attributable to injuries (mainly suicides) and substance-related mortality (mainly poisonings). In contrast, older cohorts enjoyed advantages for females in Australia and Canada and for males in all English-speaking countries except the United States. CONCLUSIONS: Although future gains in life expectancy in wealthy societies will increasingly depend on reducing mortality at older ages, adverse health trends at younger ages are a cause for concern. This emerging and avoidable threat to health equity in English-speaking countries should be the focus of further research and policy action.

Modeling Parkinson's disease pathology in human dopaminergic neurons by sequential exposure to α-synuclein fibrils and proinflammatory cytokines.

Lewy bodies (LBs), α-synuclein-enriched intracellular inclusions, are a hallmark of Parkinson's disease (PD) pathology, yet a cellular model for LB formation remains elusive. Recent evidence indicates that immune dysfunction may contribute to the development of PD. In this study, we found that induced pluripotent stem cell (iPSC)-derived human dopaminergic (DA) neurons form LB-like inclusions after treatment with α-synuclein preformed fibrils (PFFs) but only when coupled to a model of immune challenge (interferon-γ or interleukin-1ß treatment) or when co-cultured with activated microglia-like cells. Exposure to interferon-γ impairs lysosome function in DA neurons, contributing to LB formation. The knockdown of LAMP2 or the knockout of GBA in conjunction with PFF administration is sufficient for inclusion formation. Finally, we observed that the LB-like inclusions in iPSC-derived DA neurons are membrane bound, suggesting that they are not limited to the cytoplasmic compartment but may be formed due to dysfunctions in autophagy. Together, these data indicate that immune-triggered lysosomal dysfunction may contribute to the development of PD pathology.

Relationships between social determinants of health and healthy body composition among Aboriginal and Torres Strait Islander youth in the Next Generation: Youth Well-being study.

ISSUE ADDRESSED: Little is currently known about the relationships between body composition and the social determinants of health among Aboriginal and Torres Strait Islander youth in Australia, which could help inform policy responses to address health inequities. METHODS: This study aimed to explore the relationship between various social factors and healthy body mass index (BMI) and waist/height ratio (WHtR) among Aboriginal and Torres Strait Islander youth aged 16-24 years. Baseline survey data from 531 participants of the 'Next Generation: Youth Well-being study' were used. Robust Poisson regression quantified associations between healthy body composition and self-reported individual social factors (education, employment and income, government income support, food insecurity, home environment, relationship status, racism), family factors (caregiver education and employment) and area-level factors (remoteness, socioeconomic status). RESULTS: Healthy body composition was less common among those living in a crowded home (healthy WHtR aPR 0.67 [0.47-0.96]) and those receiving government income support (healthy BMI aPR 0.74 [0.57-0.95]). It was more common among those with tertiary educated caregivers (healthy BMI aPR 1.84 [1.30-2.61]; healthy WHtR aPR 1.41 [1.05-1.91]) and those in a serious relationship (healthy BMI aPR 1.33 [1.02-1.75]). CONCLUSIONS: Social factors at the individual and family level are associated with healthy body composition among Aboriginal and Torres Strait Islander youth. SO WHAT?: The findings of this study highlight the potential for health benefits for youth from policies and programs that address social inequities experienced by Aboriginal and Torres Strait Islander people in Australia.

Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) feature altered brain development, developmental delay and seizures, with seizures exacerbating developmental delay. Here we identify a cohort with biallelic variants in DENND5A, encoding a membrane trafficking protein, and develop animal models with phenotypes like the human syndrome. We demonstrate that DENND5A interacts with Pals1/MUPP1, components of the Crumbs apical polarity complex required for symmetrical division of neural progenitor cells. Human induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division with an inherent propensity to differentiate into neurons. These phenotypes result from misalignment of the mitotic spindle in apical neural progenitors. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state, ultimately shortening the period of neurogenesis. This study provides a mechanism for DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

Mental health-related service and medicine use among a cohort of urban Aboriginal children and young people: Data linkage study.

OBJECTIVE: The objective was to describe mental health service and psychotropic medicine use among a cohort of Aboriginal young people and quantify their relation to sociodemographic, family and health factors. METHODS: In a prospective cohort study with data linkage, 892 Aboriginal children aged 0-17 years living in urban and regional areas of New South Wales, Australia, were included. We assessed mental health-related service use, paediatric service use and psychotropic medicine dispensing claims covered by the Australian Government Medicare Benefits Schedule and the Pharmaceutical Benefits Scheme from July 2012 to June 2017. RESULTS: Most children (71%) did not have a record of mental health service or psychotropic medication use. 18.7% had ⩾1 mental health-related service claim; 26.7% had ⩾1 paediatric service claim; and 20.3% had ⩾1 psychotropic medicine dispensing claim. General practitioner services were the most accessed mental health-related service (17.4%) and 12.7% had been dispensed attention-deficit hyperactivity disorder medicines. Child characteristics associated with treatment included emotional and behavioural problems (prevalence ratio: 1.97, 95% confidence interval = [1.46, 2.64] for mental health services; prevalence ratio: 2.87, 95% confidence interval = [2.07, 3.96] for medicines) and risky behaviour (prevalence ratio: 1.56, 95% confidence interval = [1.12, 2.16] for mental health services; prevalence ratio: 2.28, 95% confidence interval = [1.54, 3.37] for medicines). Parent-related factors included chronic illness (prevalence ratio: 1.42, 95% confidence interval = [1.03, 1.95] for mental health services; prevalence ratio: 2.00, 95% confidence interval = [1.49, 2.69] for medicines) and functional limitations (prevalence ratio: 1.61, 95% confidence interval = [1.16, 2.24] for mental health services; prevalence ratio: 1.86, 95% confidence interval = [1.34, 2.59] for medicines). CONCLUSIONS: Most Aboriginal children and young people did not have claims for mental health services or medicines. Aboriginal children with emotional and behavioural problems, or parents with health problems were more likely to have mental health service or medicine claims.

Carrying on with life as a lung cancer survivor: a qualitative study of Australian survivors' employment, finances, relationships, and healthcare experiences.

Background: With novel therapies, more individuals are living longer with lung cancer (LC). This study aimed to understand the impacts of LC on life domains such as employment, finances, relationships, and healthcare needs. Methods: Individuals 18+, diagnosed with LC, 6-24 months post-treatment were recruited through an Australian LC cohort study (Embedding Research and Evidence in Cancer Healthcare-EnRICH). Demographic, clinical, quality-of-life and distress data were obtained through the EnRICH study database. Participants completed telephone interviews. Qualitative data were analysed via Framework methods. Results: Twenty interviews (10 females) were conducted. Most participants were diagnosed with advanced LC (Stage III =8, Stage IV =6), and were on average 17 (range, 10-24) months post-diagnosis. Four themes related to "carrying on with life" as a LC survivor were identified: (I) the winding path back to work: those working pre-diagnosis discussed challenges of maintaining/returning to employment, and the meaning and satisfaction derived from work. (II) Vulnerability versus protection: managing the financial impacts of LC: wide variations in financial impacts, some described lost income and high healthcare expenses, others felt financially protected. (III) Connection and loneliness: navigating relationships as a survivor: some experienced lost friendships due to their diagnosis, others noted more meaningful connections. (IV) Still under the umbrella: healthcare during survivorship: participants noted the importance of ongoing oncology team connection and the vital role of cancer care coordinators. Conclusions: Many individuals living with LC want to "carry on" with life. Participants spoke of challenges and opportunities across life domains of relationships, work, and finances, and noted the importance of continued specialist healthcare throughout survivorship.

Association of optimism and social support with health-related quality of life among Australian women cancer survivors - A cohort study.

AIM: Large-scale studies investigating health-related quality of life (HRQL) in cancer survivors are limited. This study aims to investigate HRQL and its relation to optimism and social support among Australian women following a cancer diagnosis. METHODS: Data were from the Australian Longitudinal Study on Women's Health, a large cohort study (n = 14,715; born 1946-51), with 1428 incident cancer cases ascertained 1996-2017 via linkage to the Australian Cancer Database. HRQL was measured using the Short Form-36 (median 1.7 years post-cancer-diagnosis). Multivariable linear regression was performed on each HRQL domain, separately for all cancers combined, major cancer sites, and cancer-free peers. RESULTS: Higher optimism and social support were significantly associated with better HRQL across various domains in women with and without a cancer diagnosis (p < 0.05). Mean HRQL scores across all domains for all cancer sites were significantly higher among optimistic versus not optimistic women with cancer (p < 0.05). Adjusting for sociodemographic and other health conditions, lower optimism was associated with reduced scores across all domains, with greater reductions in mental health (adjusted mean difference (AMD) = -11.54, p < 0.01) followed by general health (AMD = -11.08, p < 0.01). Social support was less consistently related to HRQL scores, and following adjustment was only significantly associated with social functioning (AMD = -7.22, p < 0.01) and mental health (AMD = -6.34, p < 0.01). CONCLUSIONS: Our findings highlight a strong connection between optimism, social support, and HRQL among cancer survivors. Providing psychosocial support and addressing behavioral and socioeconomic factors and other health conditions associated with optimism and social support may improve HRQL.

2023 Australian guideline for assessing and managing cardiovascular disease risk.

INTRODUCTION: The 2023 Australian guideline for assessing and managing cardiovascular disease risk provides updated evidence-based recommendations for the clinical assessment and management of cardiovascular disease (CVD) risk for primary prevention. It includes the new Australian CVD risk calculator (Aus CVD Risk Calculator), based on an equation developed from a large New Zealand cohort study, customised and recalibrated for the Australian population. The new guideline replaces the 2012 guideline that recommended CVD risk assessment using the Framingham risk equation. MAIN RECOMMENDATIONS: The new guideline recommends CVD risk assessment in people without known CVD: all people aged 45-79 years, people with diabetes from 35 years, and First Nations people from 30 years. The new Aus CVD Risk Calculator should be used to estimate and categorise CVD risk into low (< 5% risk over five years), intermediate (5% to < 10% risk over five years) or high risk (≥ 10% over five years). The following reclassification factors may be applied to recategorise calculated risk to improve accuracy of risk prediction, particularly in individuals close to a risk threshold: Indigenous status/ethnicity, estimated glomerular filtration rate, urine albumin to creatinine ratio measurements, severe mental illness, coronary artery calcium score and family history of premature CVD. A variety of communication formats is available to communicate CVD risk to help enable shared decision making. Healthy lifestyle modification, including smoking cessation, nutrition, physical activity and limiting alcohol, is encouraged for all individuals. Blood pressure-lowering and lipid-modifying pharmacotherapies should be prescribed for high risk and considered for intermediate risk individuals, unless contraindicated or clinically inappropriate. Reassessment of CVD risk should be considered within five years for individuals at low risk and within two years for those with intermediate risk. Reassessment of CVD risk is not recommended for individuals at high risk. CHANGES IN ASSESSMENT AND MANAGEMENT AS A RESULT OF THE GUIDELINE: The updated guideline recommends assessment over a broader age range and uses the Aus CVD Risk Calculator, which replaces the previous Framingham-based equation. It incorporates new variables: social disadvantage, diabetes-specific risk markers, diagnosis of atrial fibrillation and use of blood pressure-lowering and lipid-modifying therapies. Reclassification factors are also a new addition. Updated risk categories and thresholds are based on the new Aus CVD Risk Calculator. The proportion of the population in the high risk category (≥ 10% over five years) is likely to be broadly comparable to more than 15% risk from the Framingham-based equation. The full guideline and Aus CVD Risk Calculator can be accessed at www.cvdcheck.org.au.

Impact of weighting on the association between sociodemographic characteristics, health behaviours and cancer, cardiovascular and all-cause mortality in the Australian 45 and Up Study.

BACKGROUND: Weighting can improve study estimate representativeness. We examined the impact of weighting on associations between participants' characteristics and cancer, cardiovascular and all-cause mortality in the Australian 45 and Up Study cohort. METHODS: Raking weighted cohort data to the 2006 Australian population for seven sociodemographic characteristics. Deaths were ascertained via linkage to routinely collected data. Cox's proportional hazards regression quantified associations between 11 sociodemographic and health characteristics and cancer, cardiovascular and all-cause mortality. The ratios of hazard ratios (RHRs) compared unweighted and weighted estimates. RESULTS: Among 195,052 included participants (median follow-up 11.4 years), there were 7200 cancer, 5912 cardiovascular and 21,840 all-cause deaths. Overall, 102/111 (91.9%) weighted HRs did not differ significantly from unweighted HRs (100%, 86.5% and 89.2% of 37 HRs for cancer, cardiovascular and all-cause mortality, respectively). Significant differences included a somewhat stronger association between single/widowed/divorced (versus married/de-facto) and cardiovascular mortality (unweighted HR=1.25 (95%CI:1.18-1.32), weighted HR=1.33 (95%CI:1.24-1.42), RHR=1.06 (95%CI:1.02-1.11)); and between no school certificate/qualification (versus university degree) and all-cause mortality (unweighted HR=1.21 (95%CI:1.15-1.27), weighted HR=1.28 (95%CI:1.19-1.38), RHR=1.06 (95%CI:1.03-1.10)). CONCLUSION: Our results support the generalisability of most estimates of associations in the 45 and Up Study, particularly in relation to cancer mortality. Slight distortion of a few associations with cardiovascular or all-cause mortality were observed.

Electronic cigarette social norms among adolescents in New South Wales, Australia.

The use of electronic cigarettes (e-cigarettes) is common and increasing, especially among youth. In 2022/2023, 30% of 12- to 17-year-olds reported ever using e-cigarettes in Australia-a >50% increase from 2017 (14%). Several adverse e-cigarette health effects have been identified and most effects remain unknown. Social norms, rules that govern social behaviours, are associated with current and future adolescent e-cigarette use. Understanding social norms in Australian adolescents is critical to the development of targeted and effective e-cigarette prevention activities. This study aims to explore e-cigarette social norms among adolescents living in New South Wales, Australia. A total of 32 online single or paired semi-structured qualitative interviews were conducted involving 46 participants aged 14-17 years, as part of the Generation Vape project. Reflexive thematic analysis was applied within a constructivist perceptive. Adolescents perceived e-cigarettes use as prolific among their peers, with use considered common, acceptable and normal. Fuelled by social exposure to e-cigarettes, 'everyone' was generally thought to be using them (descriptive norms). E-cigarette use was considered so entrenched that it was part of adolescent identity, with abstinence regarded as atypical. Use was driven by an internalised desire to fit it (injunctive norm), rather than being attributed to overt/external 'peer-pressure'. Positive e-cigarette norms exist among Australian adolescents with norm formation strongly influenced by social exposure, including e-cigarette promotion. Prevention efforts should include limiting adolescent exposure to e-cigarette marketing to help redefine existing pro-e-cigarette social norms and protect health.

Cardiometabolic health markers among Aboriginal adolescents from the Next Generation Youth Wellbeing Cohort Study.

OBJECTIVE: The objective of this study was to investigate cardiometabolic health markers among Aboriginal adolescents aged 10-24 years and relationships with age, gender, and body composition. METHODS: Baseline data (2018-2020) from the Next Generation Youth Wellbeing Cohort Study (Western Australia, New South Wales, and Central Australia) on clinically assessed body mass index, waist/height ratio, blood pressure, glycated haemoglobin (HbA1c), total and high-density lipoprotein cholesterol, total/high-density lipoprotein cholesterol ratio, and triglycerides were analysed. RESULTS: Among 1100 participants, the proportion with individual health markers within the ideal range ranged from 59% for total cholesterol to 91% for HbA1c. Four percent had high blood pressure, which was more common with increasing age and among males; 1% had HbA1c indicative of diabetes. Healthier body composition (body mass index and waist/height ratio) was associated with having individual health markers in the ideal range and with an ideal cardiometabolic profile. CONCLUSIONS: Most Aboriginal adolescents in this study had cardiometabolic markers within the ideal range, though markers of high risk were present from early adolescence. Ideal health markers were more prevalent among those with healthy body composition. IMPLICATIONS FOR PUBLIC HEALTH: Specific screening and management guidelines for Aboriginal adolescents and population health initiatives that support maintenance of healthy body composition could help improve cardiometabolic health in this population.

Trends and projections of cause-specific premature mortality in Australia to 2044: a statistical modelling study.

Background: Long-term projections of premature mortality (defined as deaths age <75 years) help to inform decisions about public health priorities. This study aimed to project premature mortality rates in Australia to 2044, and to estimate numbers of deaths and potential years of life lost (PYLL) due to premature mortality overall and for 59 causes. Methods: We examined the past trends in premature mortality rates using Australian mortality data by sex, 5-year age group and 5-year calendar period up to 2019. Cigarette smoking exposure data (1945-2019) were included to project lung cancer mortality. Age-period-cohort or generalised linear models were developed and validated for each cause to project premature mortality rates to 2044. Findings: Over the 25-year period from 1990-1994 to 2015-2019, there was a 44.4% decrease in the overall age-standardised premature mortality rate. This decline is expected to continue, from 162.4 deaths/100,000 population in 2015-2019 to 141.7/100,000 in 2040-2044 (12.7% decrease). Despite declining rates, total numbers of premature deaths are projected to increase by 22.8%, rising from 272,815 deaths in 2015-2019 to 334,894 deaths in 2040-2044. This is expected to result in 1.58 million premature deaths over the 25-year period 2020-2044, accounting for 24.5 million PYLL. Of the high-level cause categories, cancer is projected to remain the most common cause of premature death in Australia by 2044, followed by cardiovascular disease, external causes (including injury, poisoning, and suicide), and respiratory diseases. Interpretation: Despite continuously declining overall premature mortality rates, the total number of premature deaths in Australia is projected to remain substantial, and cancer will continue to be the leading cause. These projections can inform the targeting of public health efforts and can serve as benchmarks against which to measure the impact of future interventions. They emphasise the ongoing importance of accelerating the prevention, early detection, and treatment of key health conditions. Funding: No funding was provided for this study.

Loss of symmetric cell division of apical neural progenitors drives DENND5A-related developmental and epileptic encephalopathy.

Developmental and epileptic encephalopathies (DEEs) are a heterogenous group of epilepsies in which altered brain development leads to developmental delay and seizures, with the epileptic activity further negatively impacting neurodevelopment. Identifying the underlying cause of DEEs is essential for progress toward precision therapies. Here we describe a group of individuals with biallelic variants in DENND5A and determine that variant type is correlated with disease severity. We demonstrate that DENND5A interacts with MUPP1 and PALS1, components of the Crumbs apical polarity complex, which is required for both neural progenitor cell identity and the ability of these stem cells to divide symmetrically. Induced pluripotent stem cells lacking DENND5A fail to undergo symmetric cell division during neural induction and have an inherent propensity to differentiate into neurons, and transgenic DENND5A mice, with phenotypes like the human syndrome, have an increased number of neurons in the adult subventricular zone. Disruption of symmetric cell division following loss of DENND5A results from misalignment of the mitotic spindle in apical neural progenitors. A subset of DENND5A is localized to centrosomes, which define the spindle poles during mitosis. Cells lacking DENND5A orient away from the proliferative apical domain surrounding the ventricles, biasing daughter cells towards a more fate-committed state and ultimately shortening the period of neurogenesis. This study provides a mechanism behind DENND5A-related DEE that may be generalizable to other developmental conditions and provides variant-specific clinical information for physicians and families.

DENND6A links Arl8b to a Rab34/RILP/dynein complex, regulating lysosomal positioning and autophagy.

Lysosomes help maintain cellular proteostasis, and defects in lysosomal positioning and function can cause disease, including neurodegenerative disorders. The spatiotemporal distribution of lysosomes is regulated by small GTPases including Rabs, which are activated by guanine nucleotide exchange factors (GEFs). DENN domain proteins are the largest family of Rab GEFs. Using a cell-based assay, we screened DENND6A, a member of the DENN domain protein family against all known Rabs and identified it as a potential GEF for 20 Rabs, including Rab34. Here, we demonstrate that DENND6A activates Rab34, which recruits a RILP/dynein complex to lysosomes, promoting lysosome retrograde transport. Further, we identify DENND6A as an effector of Arl8b, a major regulatory GTPase on lysosomes. We demonstrate that Arl8b recruits DENND6A to peripheral lysosomes to activate Rab34 and initiate retrograde transport, regulating nutrient-dependent lysosomal juxtanuclear repositioning. Loss of DENND6A impairs autophagic flux. Our findings support a model whereby Arl8b/DENND6A/Rab34-dependent lysosomal retrograde trafficking controls autophagy.

Health behaviours associated with healthy body composition among Aboriginal adolescents in Australia in the 'Next Generation: Youth Well-being study'.

This study described the distribution of healthy body composition among Aboriginal adolescents in Australia aged 10-24 years and examined associations with health behaviours and self-rated health. Data were cross-sectional from the 'Next Generation: Youth Well-being study' baseline (N = 1294). We used robust Poisson regression to quantify associations of self-reported health behaviours (physical activity, screen time, sleep, consumption of vegetables, fruit, soft drinks and fast food, and tobacco smoking and alcohol) and self-rated health to healthy body mass index (BMI) and waist/height ratio (WHtR). Overall, 48% of participants had healthy BMI and 64% healthy WHtR, with healthy body composition more common among younger adolescents. Higher physical activity was associated with healthy body composition (5-7 days last week vs none; adjusted prevalence ratio (aPR) healthy BMI 1.31 [95% CI 1.05-1.64], and healthy WHtR 1.30 [1.10-1.54]), as was recommended sleep duration (vs not; aPR healthy BMI 1.56 [1.19-2.05], and healthy WHtR 1.37 [1.13-1.67]). There was a trend for higher proportion of healthy body composition with more frequent fast food consumption. Healthy body composition was also associated with higher self-rated health ('very good/excellent' vs 'poor/fair'; aPR healthy BMI 1.87 [1.45-2.42], and healthy WHtR 1.71 [1.40-2.10]). Culturally appropriate community health interventions with a focus on physical activity and sleep may hold promise for improving body composition among Aboriginal adolescents.

Pain and its interference with daily living in relation to cancer: a comparative population-based study of 16,053 cancer survivors and 106,345 people without cancer.

BACKGROUND: Pain is a common, debilitating, and feared symptom, including among cancer survivors. However, large-scale population-based evidence on pain and its impact in cancer survivors is limited. We quantified the prevalence of pain in community-dwelling people with and without cancer, and its relation to physical functioning, psychological distress, and quality of life (QoL). METHODS: Questionnaire data from participants in the 45 and Up Study (Wave 2, n = 122,398, 2012-2015, mean age = 60.8 years), an Australian population-based cohort study, were linked to cancer registration data to ascertain prior cancer diagnoses. Modified Poisson regression estimated age- and sex-adjusted prevalence ratios (PRs) for bodily pain and pain sufficient to interfere with daily activities (high-impact pain) in people with versus without cancer, for 13 cancer types, overall and according to clinical, personal, and health characteristics. The relation of high-impact pain to physical and mental health outcomes was quantified in people with and without cancer. RESULTS: Overall, 34.9% (5,436/15,570) of cancer survivors and 31.3% (32,471/103,604) of participants without cancer reported bodily pain (PR = 1.07 [95% CI = 1.05-1.10]), and 15.9% (2,468/15,550) versus 13.1% (13,573/103,623), respectively, reported high-impact pain (PR = 1.13 [1.09-1.18]). Pain was greater with more recent cancer diagnosis, more advanced disease, and recent cancer treatment. High-impact pain varied by cancer type; compared to cancer-free participants, PRs were: 2.23 (1.71-2.90) for multiple myeloma; 1.87 (1.53-2.29) for lung cancer; 1.06 (0.98-1.16) for breast cancer; 1.05 (0.94-1.17) for colorectal cancer; 1.04 (0.96-1.13) for prostate cancer; and 1.02 (0.92-1.12) for melanoma. Regardless of cancer diagnosis, high-impact pain was strongly related to impaired physical functioning, psychological distress, and reduced QoL. CONCLUSIONS: Pain is common, interfering with daily life in around one-in-eight older community-dwelling participants. Pain was elevated overall in cancer survivors, particularly for certain cancer types, around diagnosis and treatment, and with advanced disease. However, pain was comparable to population levels for many common cancers, including breast, prostate and colorectal cancer, and melanoma.

DENND2B activates Rab35 at the intercellular bridge, regulating cytokinetic abscission and tetraploidy.

Cytokinesis relies on membrane trafficking pathways regulated by Rabs and guanine nucleotide exchange factors (GEFs). During cytokinesis, the intercellular cytokinetic bridge (ICB) connecting daughter cells undergoes abscission, which requires actin depolymerization. Rab35 recruits MICAL1 to oxidize and depolymerize actin filaments. We show that DENND2B, a protein linked to cancer and congenital disorders, functions as a Rab35 GEF, recruiting and activating Rab35 at the ICB. DENND2B's N-terminal region also interacts with an active form of Rab35, suggesting that DENND2B is both a Rab35 GEF and effector. Knockdown of DENND2B delays abscission, leading to multinucleated cells and filamentous actin (F-actin) accumulation at the ICB, impairing recruitment of ESCRT-III at the abscission site. Additionally, F-actin accumulation triggers the formation of a chromatin bridge, activating the NoCut/abscission checkpoint, and DENND2B knockdown activates Aurora B kinase, a hallmark of checkpoint activation. Thus, our study identifies DENND2B as a crucial player in cytokinetic abscission.

Ear health and hearing in urban Aboriginal children.

OBJECTIVE: Evaluate ear health and hearing among urban Aboriginal children and quantify relationships with child, family and social factors. METHODS: Baseline questionnaire and ear health examinations from 1430 children with diagnoses (0.5-18 years) attending Aboriginal Health Services enrolled in SEARCH. Ear health outcomes were Otitis Media (OM), and hearing loss (three-frequency average hearing loss >20dB) diagnosed using pneumatic otoscopy, tympanometry, and audiometry. RESULTS: Half the children 0.5-3 years had OM (51.5%, 136/264). One third 0.5-18 years (30.4%; 435/1430) had OM, including 1.8% (26/1430) with perforation (0.8% chronic suppurative OM, 0.6% dry perforation and 0.4% acute OM with perforation). One quarter 0.5-18 years (25.7%; 279/1087) had hearing loss; 12.4% unilateral, 13.2% bilateral (70.6% with bilateral loss had concurrent OM). OM was associated with: younger age (0.5-<3 years versus 6-18 years) age-sex-site; adjusted prevalence ratio (aPR)=2.64, 95%, 2.18-3.19); attending childcare/preschool (aPR=1.24, 95%CI, 1.04-1.49); foster care (aPR=1.40, 95%CI, 1.10-1.79); previous ear infection/s (aPR=1.68, 95%CI, 1.42-1.98); and ≥2 people/bedroom (aPR=1.66, 95%CI, 1.24-2.21). Hearing impairment was associated with younger age (0.5-<6 years vs. ≥6 years aPR=1.89, 95%CI, 1.40-2.55) and previous ear infection (aPR=1.87, 95%CI, 1.31-2.68). CONCLUSIONS: Half the urban Aboriginal children in this cohort had OM and two-thirds with hearing impairment had OM. IMPLICATIONS FOR PUBLIC HEALTH: Findings highlight importance of early detection and support for ear health, particularly in pre-school-aged children with risk factors.

Application of a revised model for coping with advanced cancer to qualitatively explore lung cancer survivors' experiences of ongoing physical effects, novel treatments, uncertainty, and coping.

PURPOSE: Lung cancer remains underrepresented in cancer survivorship research. This study aimed to understand survivors' physical/psychological challenges, experiences of immunotherapy (IO) and targeted therapy (TT), and psychological adjustment through application of the Roberts et al. (2017) advanced cancer adaptation of Folkman and Greer's appraisal and coping model. METHODS: Adults 6-24 months post-initial treatment completion were recruited via an Australian cohort study. Participant demographic, clinical, quality of life, and distress data were obtained through the cohort database. Qualitative interviews were conducted and analyzed using Framework methods. Roberts et al. (2017)'s model informed data interpretation and presentation. RESULTS: Twenty interviews were conducted (10 females; average age 69 years). Participants' diagnostic stages varied (stage I = 2, stage II = 4, stage III = 8, stage IV = 6); most had received IO/TT (n = 14) and were on average 17 months (range 10-24) post-diagnosis. Three themes were identified and mapped to the Roberts' framework: (1) Ongoing illness events: most participants reported functioning well despite ongoing physical effects. Those on IO/TT reported side effects; some were unexpected/serious. (2) Adjusting to life with lung cancer: most expressed hope for the future while simultaneously preparing for disease progression. Those receiving IO/TT experienced uncertainty given limited survival information. (3) Learning to live with lung cancer: participants described emotion, problem, and meaning based on coping strategies. CONCLUSIONS: Findings may guide development of supportive care resources/interventions focused on uncertainty, IO/TT communication and decision-making, and coping. IMPLICATIONS FOR CANCER SURVIVORS: Many people with lung cancer are living well with their ongoing illness. Despite challenges, many survivors are adapting to issues as they arise and are maintaining a sense of hope and optimism.

Evidence supporting the choice of a new cardiovascular risk equation for Australia.

This article reviews the risk equations recommended for use in international cardiovascular disease (CVD) primary prevention guidelines and assesses their suitability for use in Australia against a set of a priori defined selection criteria. The review and assessment were commissioned by the National Heart Foundation of Australia on behalf of the Australian Chronic Disease Prevention Alliance to inform recommendations on CVD risk estimation as part of the 2023 update of the Australian CVD risk assessment and management guidelines. Selected international risk equations were assessed against eight selection criteria: development using contemporary data; inclusion of established cardiovascular risk factors; inclusion of ethnicity and deprivation measures; prediction of a broad selection of fatal and non-fatal CVD outcomes; population representativeness; model performance; external validation in an Australian dataset; and the ability to be recalibrated or modified. Of the ten risk prediction equations reviewed, the New Zealand PREDICT equation met seven of the eight selection criteria, and met additional usability criteria aimed at assessing the ability to apply the risk equation in practice in Australia.