Population-level utilisation of neoadjuvant radiotherapy for the treatment of rectal cancer.

PURPOSE: International clinical guidelines recommend long- or short-course neoadjuvant radiotherapy for locally advanced rectal cancer. This study aims to examine variation in the use of neoadjuvant radiotherapy for rectal cancer and identify patient and hospital factors that underpin this variation. METHODS AND MATERIALS: We conducted a retrospective, consecutive cohort study using statewide hospitalisation and radiotherapy data from New South Wales, Australia, 2013-2018. Included participants had a primary rectal adenocarcinoma and underwent surgical resection. Factors associated with the use or not of any neoadjuvant radiotherapy, and short versus long-course were explored using multilevel logistic regression models. RESULTS: Of the 2912 people included in the study, 43% received neoadjuvant radiotherapy. There was significant variation in the use of neoadjuvant radiotherapy depending on geographic location. Abdominoperineal excision (odds ratio [OR] = 1.87, 95% confidence interval [CI] = 1.53-2.28) and having surgery in a public hospital (OR = 2.34, 95% CI = 1.92-2.87) were both predictors of use. Among those receiving neoadjuvant radiotherapy, 17% received short-course therapy, with short-course declining over the study period. CONCLUSIONS: The use of neoadjuvant radiotherapy for rectal cancer is highly variable, with differences only partially explained by assessable patient-or hospital-level factors. Understanding neoadjuvant radiotherapy utilisation patterns may assist in identifying barriers and opportunities to improve adherence to clinical guidelines.

Is mode of first birth a risk factor for subsequent preterm birth?

BACKGROUND: Previous preterm birth is a strong predictor of subsequent preterm birth, but less is known about the causes of preterm birth following a full-term first pregnancy. Recent research has highlighted previous caesarean section as a potential risk factor. AIM: To examine the relationship between mode of first birth and the risk of subsequent preterm birth in New South Wales (NSW), Australia. MATERIALS AND METHODS: A population-based record-linkage study of NSW women who had a live singleton first birth at ≥37 weeks gestation, followed by a singleton second birth between 2005 and 2017. Relative risk (RR) and 95% CI of preterm birth in the subsequent pregnancy was calculated using modified Poisson regression, with mode of first birth as the exposure. Spontaneous preterm birth and preterm prelabour caesarean were secondary outcomes. RESULTS: Women who had either an intrapartum (RR: 1.26, 95% CI 1.19-1.32) or prelabour caesarean (RR: 1.26, 95% CI 1.18-1.35) first birth had a higher risk of subsequent preterm birth (any birth <37 weeks gestation), than those who birthed vaginally. Women who had a previous instrumental birth (RR: 0.85, 95% CI 0.79-0.91) or prelabour caesarean (RR: 0.74, 95% CI 0.67-0.82) had lower risks of subsequent spontaneous preterm birth. However, prior prelabour caesarean also greatly increased risk of subsequent preterm prelabour caesarean (RR: 5.25, 95% CI 4.65-5.93). CONCLUSIONS: The mode of first birth has differing effects on the risk of subsequent spontaneous preterm birth and preterm prelabour caesarean. Awareness of the risk of subsequent preterm birth following caesarean section may help inform clinical decisions around mode of first birth.

Randomised Controlled Trial (RCT) of cannabinoid replacement therapy (Nabiximols) for the management of treatment-resistant cannabis dependent patients: a study protocol.

BACKGROUND: The cannabis extract nabiximols (Sativex®) effectively supresses withdrawal symptoms and cravings in treatment resistant cannabis dependent individuals, who have high relapse rates following conventional withdrawal treatments. This study examines the efficacy, safety and cost-effectiveness of longer-term nabiximols treatment for outpatient cannabis dependent patients who have not responded to previous conventional treatment approaches. METHODS/DESIGN: A phase III multi-site outpatient, randomised, double-blinded, placebo controlled parallel design, comparing a 12-week course of nabiximols to placebo, with follow up at 24 weeks after enrolment. Four specialist drug and alcohol outpatient clinics in New South Wales, Australia. One hundred forty-two treatment seeking cannabis dependent adults, with no significant medical, psychiatric or other substance use disorders. Nabiximols is an oromucosal spray prescribed on a flexible dose regimen to a maximum daily dose of 32 sprays; 8 sprays (total 21.6 mg tetrahydrocannabinol (THC) and 20 mg cannabidiol (CBD)) four times a day, or matching placebo, dispensed weekly. All participants will receive six-sessions of individual cognitive behavioural therapy (CBT) and weekly clinical reviews. Primary endpoints are use of non-prescribed cannabis (self-reported cannabis use days, urine toxicology), safety measures (adverse events and abuse liability), and cost effectiveness (incremental cost effectiveness in achieving additional Quality Adjusted Life Years). Secondary outcomes include, improvement in physical and mental health parameters, substance use other than cannabis, cognitive functioning and patient satisfaction measures. DISCUSSION: This is the first outpatient community-based randomised controlled study of nabiximols as an agonist replacement medication for treating cannabis dependence, targeting individuals who have not previously responded to conventional treatment approaches. The study and treatment design is modelled upon an earlier study with this population and more generally on other agonist replacement treatments (e.g. nicotine, opioids). TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12616000103460 (Registered 1st February 2016).

The early origins of food preferences: targeting the critical windows of development.

The nutritional environment to which an individual is exposed during the perinatal period plays a crucial role in determining his or her future metabolic health outcomes. Studies in rodent models have demonstrated that excess maternal intake of high-fat and/or high-sugar "junk foods" during pregnancy and lactation can alter the development of the central reward pathway, particularly the opioid and dopamine systems, and program an increased preference for junk foods in the offspring. More recently, there have been attempts to define the critical windows of development during which the opioid and dopamine systems within the reward pathway are most susceptible to alteration and to determine whether it is possible to reverse these effects through nutritional interventions applied later in development. This review discusses the progress made to date in these areas, highlights the apparent importance of sex in determining these effects, and considers the potential implications of the findings from rodent models in the human context.

A maternal "junk-food" diet reduces sensitivity to the opioid antagonist naloxone in offspring postweaning.

Perinatal exposure to a maternal "junk-food" diet has been demonstrated to increase the preference for palatable diets in adult offspring. We aimed to determine whether this increased preference could be attributed to changes in µ-opioid receptor expression within the mesolimbic reward pathway. We report here that mRNA expression of the µ-opioid receptor in the ventral tegmental area (VTA) at weaning was 1.4-fold (males) and 1.9-fold (females) lower in offspring of junk-food (JF)-fed rat dams than in offspring of dams fed a standard rodent diet (control) (P<0.05). Administration of the opioid antagonist naloxone to offspring given a palatable diet postweaning significantly reduced fat intake in control offspring (males: 7.7 ± 0.7 vs. 5.4 ± 0.6 g/kg/d; females: 6.9 ± 0.3 vs. 3.9 ± 0.5 g/kg/d; P<0.05), but not in male JF offspring (8.6 ± 0.6 vs. 7.1 ± 0.5 g/kg/d) and was less effective at reducing fat intake in JF females (42.2 ± 6.0 vs. 23.1 ± 4.1% reduction, P<0.05). Similar findings were observed for total energy intake. Naloxone treatment did not affect intake of standard rodent feed in control or JF offspring. These findings suggest that exposure to a maternal junk-food diet results in early desensitization of the opioid system which may explain the increased preference for junk food in these offspring.

Nutritional approaches to breaking the intergenerational cycle of obesity.

The link between poor maternal nutrition and an increased burden of disease in subsequent generations has been widely demonstrated in both human and animal studies. Historically, the nutritional challenges experienced by pregnant and lactating women were largely those of insufficient calories and severe micronutrient deficiencies. More recently, however, Western societies have been confronted with a new nutritional challenge; that of maternal obesity and excessive maternal intake of calories, fat, and sugar. Exposure of the developing fetus and infant to this obesogenic environment results in an increased risk of obesity and metabolic disease later in life. Furthermore, increased caloric, fat, and sugar intake can occur in conjunction with micronutrient deficiency, which may further exacerbate these programming effects. In light of the current epidemic of obesity and metabolic disease, attention has now turned to identifying nutritional interventions for breaking this intergenerational obesity cycle. In this review, we discuss the approaches that have been explored to date and highlight the need for further research.

The Effect of a Personalized Oral Health Education Program on Periodontal Health in an At-Risk Population: A Randomized Controlled Trial.

While periodontal disease is associated with many risk factors, socioeconomically disadvantaged communities experience the highest disease burden. The aim of this study was to evaluate the effectiveness of a personalized oral health education program, in combination with routine dental treatment, in participants from a low socioeconomic community. We used a randomized, controlled, examiner-blinded clinical trial. A total of 579 participants (aged 18-60 years) were randomly grouped: the intervention group (n = 292) received a personalized oral health education program in combination with routine dental care and the control group (n = 287) received routine dental care. All participants were assessed for improvement in oral health care behaviors, dental plaque, and periodontal status at baseline, 12 months, and 24 months. We found a significant drop (p < 0.001) in the plaque indices, Periodontal Probing Depths (PPD) and Bleeding on Probing (BOP) between baseline and the 12-month follow-up for both groups. For BOP, the number of sites positive was significantly different between baseline and the 24-month follow-up (p = 0.037). No differences were found between the two groups for any evaluated clinical outcome. The personalized oral health education program used in the current study did not appear to add significant improvement to clinical outcomes of periodontal health compared with routine restorative dental care per se.

Periconception and First Trimester Diet Modifies Appetite, Hypothalamic Gene Expression, and Carcass Traits in Bulls.

Nulliparous yearling beef heifers (n=360) were used to evaluate the effects of maternal dietary protein during the periconception and first trimester periods of gestation on postnatal growth, feedlot performance, carcass characteristics, and the expression of genes associated with appetite in the arcuate nucleus of their male progeny. Heifers were individually fed a diet of 1.18g crude protein (CP)/day High protein (HPeri) or 0.62g CP/day Low protein (LPeri) beginning 60days before conception. From 24 to 98days post-conception (dpc), half of each treatment group changed to the alternative post-conception diet and were fed 1.49g CP/day (HPost) or 0.88g CP/day (LPost) yielding four treatment groups in a 2×2 factorial design. From day 98 of gestation, heifers received a common diet until parturition. Calves were weaned at 183days and developed on pasture before feedlot entry. Bulls underwent a 70-day Residual Feed Intake (RFI) feedlot test commencing at 528days of age. Feedlot entry and final body weight (BW), feedlot average daily gain (ADG) and RFI were not different (p>0.05). Progeny of dams that had a change in diet (LPeri/HPost and HPeri/LPost) had 9% higher daily dry matter intake (DMI) during the RFI test (p<0.05) than progeny of dams that received low diet throughout both the peri-conception period and first trimester (LPeri/LPost). Further, mRNA expression of the appetite-stimulating agouti-related protein (AGRP) was increased in the arcuate nucleus of High Peri/LPost bulls (p<0.05). Longissimus dorsi muscle cross sectional area, carcass dressing percentage, and estimated retail beef yield (RBY) were all higher (p<0.05), and rump (P8) fat tended to be lower (p=0.07), for bulls from HPost dams despite no difference in carcass weight (p<0.05). This study is of commercial importance to the livestock industry as specific periods of maternal dietary supplementation may increase feed intake, enhance progeny muscling, and alter fat deposition leading to improvement in efficiency of meat production in beef cattle.

Effectiveness and acceptability of a text message intervention (DTEXT) on HbA1c and self-management for people with type 2 diabetes. A randomized controlled trial.

OBJECTIVE: Determine the effectiveness and acceptability of a text message intervention (DTEXT) on HbA1c and self-management behaviors for Australian adults with type 2 diabetes. METHODS: Using intention to treat analysis and generalized estimating equations, this randomized controlled trial of 395 adults determined change in HbA1c at 3 and 6 months between the intervention and control group. Secondary outcomes included change in nutrition, physical activity, blood lipid profile, body mass index, quality of life, self-efficacy, medication taking and program acceptability. RESULTS: No significant difference was observed between the intervention or control group for HbA1c at 3 months (P = 0.23) or 6 months (P = 0.22). Significant improvements were seen in consumption of vegetables at 3 months (P < 0.001) and 6 months (P = 0.04); fruit at 3 months (P = 0.046) and discretionary sweet foods at 3 months (P = 0.02). No other significant effects seen. The intervention demonstrated high rates of acceptability (94.0%) and minimal withdrawal (1.5%). CONCLUSIONS: DTEXT was an acceptable text message intervention that improved some nutritional behaviors in people with type 2 diabetes, but did not significantly improve HbA1c or other outcomes. Further research is required to optimize DTEXT. PRACTICE IMPLICATIONS: DTEXT provides an acceptable, feasible form of self-management support that may complement existing diabetes care.

Healthy Lifestyle Behaviours Are Associated with Children's Psychological Health: A Cross-Sectional Study.

Protecting children's mental health is important and studies have shown that diet and exercise can have a positive impact. There are limited data available, however, from representative populations of children on the relationship between regular healthy lifestyle behaviours and psychological health. Data were obtained from the New South Wales Child Population Health Survey, 2013-2014. Parents were asked about diet, physical activity and screen time behaviours and completed the Strengths and Difficulties Questionnaire (SDQ) for one child aged 5-15. Higher SDQ scores indicate poorer psychological health and risk for mental health problems. Multivariable linear and logistic regression examined the relationships among dietary consumption, physical activity, screen time and SDQ scores, adjusting for potential confounding. Meeting screen time recommendations was most strongly associated with a lower SDQ total difficulties score (5-10 years: -1.56 (-2.68, -0.44); 11-15 years: -2.12 (-3.11, -1.12)). Children and adolescents who met screen time recommendations were also significantly less likely to have any score in the at-risk range. Children and adolescents meeting vegetable intake guidelines had significantly lower total difficulties scores (5-10 years: -1.54 (-3.03, -0.05); 11-15 years: -1.19 (-3.60, -0.39)), as did adolescents meeting discretionary food guidelines (-1.16 (-2.14, -0.18)) and children consuming the recommended fruit intake (-1.26 (-2.42, -0.10)). Our findings indicate that more effective interventions to increase the proportion of young Australians who meet the guidelines for diet and screen time would contribute to protecting their mental health.

Prioritising Housing Maintenance to Improve Health in Indigenous Communities in NSW over 20 years.

Many studies document the relationship between housing quality and health status. Poor housing in Aboriginal communities continues to be linked to the compromised health status of Aboriginal Australians. The New South Wales (NSW) Housing for Health (HfH) program has been assessing and repairing Aboriginal community housing across the state for 20 years using a standardised intervention methodology that aims to improve the health of Aboriginal people in NSW by improving their living environments. Items are tested and repairs are prioritised to maximise safety and health benefits and measured against 11 Critical Healthy Living Priorities (e.g., safety, facilities for washing people and clothes, removing waste and preparing food). Descriptive analysis of data collected pre- and post-intervention from 3670 houses was conducted to determine the effectiveness of the program. Analysis demonstrated statistically significant improvements in the ability of the houses to support safe and healthy living for all critical healthy living priorities post-interventions. Trend analysis demonstrated the magnitude of these improvements increased over 20 years. In 24 communities (n = 802 houses) where projects were repeated (5-17 years later), results indicate sustainability of improvements for 9 of 11 priorities. However, the overall condition of health-related hardware in Aboriginal community housing across NSW pre-intervention has not significantly changed during the program's 20 years. Results suggest a systematic lack of routine maintenance and quality control continues to be the overwhelming cause for this lack of improvement pre-intervention. Our evaluation of the HfH program demonstrated that fidelity to a standardised housing testing and repair methodology to improve residents' safety and health can have sustainable effects on housing infrastructure and associated health benefits, such as a 40% reduction in infectious disease hospital separations. Housing and health agencies should collaborate more closely on social housing programs and ensure programs are adequately resourced to address safety and health issues.

Trends in Walking, Moderate, and Vigorous Physical Activity Participation Across the Socioeconomic Gradient in New South Wales, Australia From 2002 to 2015.

BACKGROUND: A combination of walking, other moderate physical activity, and vigorous physical activity is recommended for achieving good health. Vigorous activity has unique health benefits but may be less accessible to disadvantaged people. To reduce health inequity, we need to understand the differences in physical activity participation among socioeconomic subgroups and whether this is changing over time. METHODS: Data from the 2002 to 2015 Adult New South Wales Population Health Surveys (164,652 responses) were analyzed to investigate trends in walking, moderate and vigorous physical activity participation by socioeconomic status as measured by educational attainment. Analysis used age- and sex-adjusted multivariable linear models that accounted for complex survey design. RESULTS: In 2002, the highest socioeconomic group spent 18.5 (95% confidence interval, 8.2-28.8) minutes per week more than the lowest socioeconomic group being vigorously active. By 2015, this gap had steadily increased to 41.4 (95% confidence interval, 27.6-55.1) minutes per week. Inequity between groups was also found for duration of moderate activity but not for time spent walking. CONCLUSIONS: Low participation in vigorous activity in the lowest socioeconomic group is likely driving increasing inequities in physical activity and widening participation gaps over time. Barriers preventing the most disadvantaged people in New South Wales from engaging in vigorous activity should be addressed urgently.

Nabiximols for the Treatment of Cannabis Dependence: A Randomized Clinical Trial.

IMPORTANCE: There are no effective medications for treating dependence on cannabis. OBJECTIVE: To examine the safety and efficacy of nabiximols in the treatment of patients with cannabis dependence. DESIGN, SETTING, AND PARTICIPANTS: This parallel double-blind randomized clinical trial comparing nabiximols with placebo in a 12-week, multisite outpatient study recruited participants from February 3, 2016, to June 14, 2017, at 4 outpatient specialist alcohol and drug treatment services in New South Wales, Australia. Participants had cannabis dependence (as defined by the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision) and were seeking treatment, were nonresponsive to prior treatment attempts, were 18 to 64 years of age, had no other substance use disorder, had no severe medical or psychiatric conditions, were not pregnant, were not mandated by a court to undergo treatment, and provided informed consent. Results for primary efficacy measures and all secondary outcomes were obtained using a modified intention-to-treat data set. INTERVENTIONS: Participants received 12-week treatment involving weekly clinical reviews, structured counseling, and flexible medication doses-up to 32 sprays daily (tetrahydrocannabinol, 86.4 mg, and cannabidiol, 80 mg), dispensed weekly. MAIN OUTCOMES AND MEASURES: Primary outcome was self-reported number of days using illicit cannabis during the 12-week period. Other outcomes included alternate cannabis use parameters (periods of abstinence, withdrawal, cravings, and problems), safety parameters (adverse events and aberrant medication use), health status, other substance use, and treatment retention. RESULTS: A total of 128 participants (30 women and 98 men; mean [SD] age, 35.0 [10.9] years) were randomized and received at least 1 dose of study medication. Participants had used a mean (SD) of 2.3 (2.1) g of cannabis on a mean (SD) of 25.7 (4.5) days in the past 28 days. Treatment retention was comparable for the 2 groups (placebo, 30 of 67 participants [44.8%]; nabiximols, 30 of 61 participants [49.2%]), and both groups used similar mean (SD) doses (placebo, 18.5 [9.5] sprays daily; nabiximols, 17.6 [9.5] sprays daily, equivalent to a mean [SD] of 47.5 [25.7] mg of tetrahydrocannabinol and 44.0 [23.8] mg of cannabidiol). For the primary end point, the placebo group reported significantly more days using cannabis during the 12 weeks (mean [SD], 53.1 [33.0] days) than the nabiximols group (mean [SD], 35.0 [32.4] days; estimated difference, 18.6 days; 95% CI, 3.5-33.7 days; P = .02). Both groups showed comparable improvements in health status, with no substantial changes in other substance use. Medication was well tolerated with few adverse events. CONCLUSIONS AND RELEVANCE: This study demonstrates that cannabinoid agonist treatment, in this case using nabiximols, in combination with psychosocial interventions is a safe approach for reducing cannabis use among individuals with cannabis dependence who are seeking treatment. TRIAL REGISTRATION: anzctr.org.au Identifier: ACTRN12616000103460.

Sex and age-dependent effects of a maternal junk food diet on the mu-opioid receptor in rat offspring.

Perinatal junk food exposure increases the preference for palatable diets in juvenile and adult rat offspring. Previous studies have implicated reduced sensitivity of the opioid pathway in the programming of food preferences; however it is not known when during development these changes in opioid signalling first emerge. This study aimed to determine the impact of a maternal junk food (JF) diet on mu-opioid receptor (MuR) expression and ligand binding in two key regions of the reward pathway, the nucleus accumbens (NAc) and the ventral tegmental area (VTA) in rats during the early suckling (postnatal day (PND) 1 and 7) and late suckling/early post-weaning (PND 21 and 28) periods. Female rats were fed either a JF or a control diet for two weeks prior to mating and throughout pregnancy and lactation. MuR expression in the VTA was significantly reduced in female JF offspring on PND 21 and 28 (by 32% and 57% respectively, P<0.05), but not at earlier time points (PND 1 and 7). MuR ligand binding was also reduced (by 22%, P<0.05) in the VTA of female JF offspring on PND 28. No effects of perinatal junk food exposure on MuR mRNA expression or binding were detected at these time points in male offspring. These findings provide evidence that the opioid signalling system is a target of developmental programming by the end of the third postnatal week in females, but not in males.

Pregnancy, obesity and insulin resistance: maternal overnutrition and the target windows of fetal development.

A substantial body of literature has demonstrated that the nutritional environment an individual experiences before birth or in early infancy is a key determinant of their health outcomes across the life course. This concept, the developmental origins of health and disease (DOHaD) hypothesis, was initially focused on the adverse consequences of exposure to a suboptimal nutrient supply and provided evidence that maternal undernutrition, fetal growth restriction, and low birth weight were associated with heightened risk of central adiposity, insulin resistance, and cardiovascular disease. More recently, the epidemic rise in the incidence of maternal obesity has seen the attention of the DOHaD field turn toward identifying the impact on the offspring of exposure to an excess nutrient supply in early life. The association between maternal obesity and increased risk of obesity in the offspring has been documented in human populations worldwide, and animal models have provided critical insights into the biological mechanisms that drive this relationship. This review will discuss the important roles that programming of the adipocyte and programming of the central neural networks which control appetite and reward play in the early life programming of metabolic disease by maternal overnutrition. It will also highlight the important research gaps and challenges that remain to be addressed and provide a personal perspective on where the field should be heading in the coming 5-10 years.