Circadian patterns of behaviour change during pregnancy in mice.

Food intake and activity adapt during pregnancy to meet the increased energy demands. In comparison to non-pregnant females, pregnant mice consume more food, eating larger meals during the light phase, and reduce physical activity. How pregnancy changes the circadian timing of behaviour was less clear. We therefore randomised female C57BL/6J mice to mating for study until early (n = 10), mid- (n = 10) or late pregnancy (n = 11) or as age-matched, non-pregnant controls (n = 12). Mice were housed individually in Promethion cages with a 12 h light-12 h dark cycle [lights on at 07.00 h, Zeitgeber (ZT)0] for behavioural analysis. Food intake between ZT10 and ZT11 was greater in pregnant than non-pregnant mice on days 6.5-12.5 and 12.5-17.5. In mice that exhibited a peak in the last 4 h of the light phase (ZT8-ZT12), peaks were delayed by 1.6 h in the pregnant compared with the non-pregnant group. Food intake immediately after dark-phase onset (ZT13-ZT14) was greater in the pregnant than non-pregnant group during days 12.5-17.5. Water intake patterns corresponded to food intake. From days 0.5-6.5 onwards, the pregnant group moved less during the dark phase, with decreased probability of being awake, in comparison to the non-pregnant group. The onset of dark-phase activity, peaks in activity, and wakefulness were all delayed during pregnancy. In conclusion, increased food intake during pregnancy reflects increased amplitude of eating behaviour, without longer duration. Decreases in activity also contribute to positive energy balance in pregnancy, with delays to all measured behaviours evident from mid-pregnancy onwards. KEY POINTS: Circadian rhythms synchronise daily behaviours including eating, drinking and sleep, but how these change in pregnancy is unclear. Food intake increased, with delays in peaks of food intake behaviour late in the light phase from days 6.5 to 12.5 of pregnancy, in comparison to the non-pregnant group. The onset of activity after lights off (dark phase) was delayed in pregnant compared with non-pregnant mice. Activity decreased by ∼70% in the pregnant group, particularly in the dark (active) phase, with delays in peaks of wakefulness evident from days 0.5-6.5 of pregnancy onwards. These behavioural changes contribute to positive energy balance during pregnancy. Delays in circadian behaviours during mouse pregnancy were time period and pregnancy stage specific, implying different regulatory mechanisms.

Impact of bariatric surgery, lifestyle change, and pharmacotherapy on fertility in men with obesity: a systematic review protocol.

OBJECTIVE: This review will determine whether various health interventions designed to reduce weight (lifestyle change, bariatric surgery, pharmacotherapy) in men with obesity are associated with improved fertility markers. The review will also establish whether the degree of weight loss achieved through these methods is associated with improvement. BACKGROUND: Current preconception guidelines provide limited information for men with obesity. Small studies implementing lifestyle changes in men are associated with improvement in sperm quality, whereas bariatric surgery has not been associated with improvements in sperm quality. Determining the benefit of different interventions and the relationship to weight lost is necessary to optimize male fertility. INCLUSION CRITERIA: The population will be men < 50 years who are either overweight (BMI > 25 kg/m2) or obese (BMI > 30 kg/m2). The exposure of interest will be an intervention undertaken to improve health or reduce weight, categorized as lifestyle change, bariatric surgery, or pharmacotherapy. Outcomes will include time to conception, fecundity rate, assisted reproduction outcomes, and semen quality measures. Secondary analysis will determine whether degree of weight loss achieved is associated with degree of improvement. METHODS: This review will follow the JBI methodology for systematic reviews of etiology and risk. Databases to be searched will include PubMed, Embase (Ovid), Cochrane Central Register of Controlled Trials, Web of Science, and Scopus. Articles not translated into English will be excluded. Methodological quality will be assessed using the JBI critical appraisal tools. Data will be extracted using a standardized tool developed by the reviewers. Statistical meta-analysis will be performed where possible to synthesize outcomes of similar methods. REVIEW REGISTRATION NUMBER: PROSPERO CRD 42022349665.

External validation of predictive models of sexual, urinary, bowel and hormonal function after surgery in prostate cancer subjects.

BACKGROUND: In 2020, a research group published five linear longitudinal models, predict Expanded Prostate Cancer Index Composite-26 (EPIC-26) scores post-treatment for radical prostatectomy, external beam radiotherapy and active surveillance collectively in US patients with localized prostate cancer. METHODS: Our study externally validates the five prediction models for patient reported outcomes post-surgery for localised prostate cancer. The models' calibration, fit, variance explained and discrimination (concordance-indices) were assessed. Two Australian validation cohorts 1 and 2 years post-prostatectomy were constructed, consisting of 669 and 439 subjects, respectively (750 in total). Patient reported function in five domains post-prostatectomy: sexual, bowel, hormonal, urinary incontinence and other urinary dysfunction (irritation/obstruction). Domain function was assessed using the EPIC-26 questionnaire. RESULTS: 1 year post-surgery, R2 was highest for the sexual domain (35%, SD = 0.02), lower for the bowel (21%, SD = 0.03) and hormone (15%, SD = 0.03) domains, and close to zero for urinary incontinence (1%, SD = 0.01) and irritation/obstruction (- 5%, SD = 0.04). Calibration slopes for these five models were 1.04 (SD = 0.04), 0.84 (SD = 0.06), 0.85 (SD = 0.06), 1.16 (SD = 0.13) and 0.45 (SD = 0.04), respectively. Calibration-in-the-large values were - 2.2 (SD = 0.6), 2.1 (SD = 0.01), 5.1 (SD = 0.1), 9.6 (SD = 0.9) and 4.0 (SD = 0.2), respectively. Concordance-indices were 0.73, 0.70, 0.70, 0.58 and 0.62, respectively (all had SD = 0.01). Mean absolute error and root mean square error were similar across the validation and development cohorts. The validation measures were largely similar at 2 years post-surgery. CONCLUSIONS: The sexual, bowel and hormone domain models validated well and show promise for accurately predicting patient reported outcomes in a non-US surgical population. The urinary domain models validated poorly and may require recalibration or revision.

Childhood trauma histories in men and women assessed by the childhood attachment and relational trauma screen (CARTS) and the global psychotrauma screen (GPS): Results from the global collaboration on traumatic stress (GC-TS).

BACKGROUND: Whether there are biological sex differences in rates of childhood trauma exposure perpetrated by female versus male biological parents remains largely unknown. Moreover, the relative risk posed by various vulnerability factors for transdiagnostic mental health outcomes among females vs. males in adulthood has received insufficient attention. OBJECTIVE: To compare biological sex differences in the long-term impact of childhood abuse and neglect on transdiagnostic mental health outcomes, especially comparing the outcomes of childhood maltreatment perpetrated by biological mothers vs. fathers. PARTICIPANTS AND SETTING: 3129 participants (2784 female [89 %]) were recruited online, the majority (82 %) of whom endorsed having a childhood trauma history and a high number of mental health problems. METHODS: Online surveys were administered. Specifically, the Childhood Attachment and Relational Trauma Screen (CARTS) was completed as a relationally-contextualized screening measure of both positive and traumatic-neglectful experiences during childhood, comparing severity of perpetration by male vs. female biological parents. Further, the Global Psychotrauma Screen (GPS) was completed to assess the relative risk of five vulnerability factors, including childhood abuse and neglect, for long-term transdiagnostic mental health outcomes. Statistical analyses elucidate group differences between males and females primarily by way of t-tests and associated effect sizes (Cohen's d). RESULTS: Biological sex differences were shown for childhood maltreatment perpetration by male vs. female biological parents, wherein responses to CARTS showed that females reported that their biological mothers exhibited less positivity (d = 0.21), less attachment security (d = 0.22), more negative feelings toward them (d = 0.28), were more emotionally abusive (d = 0.17), and held more negative relational beliefs about them (d = 0.24). Comparably, males reported that their biological fathers were more physically abusive (d = 0.15) and that they held more negative relational beliefs toward their fathers (d = 0.25). Risk factors including having a history of childhood trauma and neglect were associated with transdiagnostic mental health problems among both females (d = 0.57) and males (d = 0.46), with other risk factors evidencing similar results. CONCLUSIONS: Childhood trauma and neglect is a risk factor for transdiagnostic mental health outcomes among both females and males, although the two biological sexes may exhibit different levels of risk of being maltreated by female and male biological parents. Specifically, females reported having more emotionally abusive biological mothers, while males reported having more physically abusive biological fathers.

Clinical outcomes for men with positive surgical margins after radical prostatectomy-results from the South Australian Prostate Cancer Clinical Outcomes Collaborative community-based registry.

Objective: Positive surgical margins (PSMs) after radical prostatectomy (RP) indicate failure of surgery to completely clear cancer. PSMs confer an increased risk of biochemical recurrence (BCR), but how more robust outcomes are affected is unclear. This study investigated factors associated with PSMs following RP and determined their impact on clinical outcomes (BCR, second treatment [radiotherapy and/or androgen deprivation therapy], and prostate cancer-specific mortality [PCSM]). Methods: The study cohort included men diagnosed with prostate cancer (pT2-3b/N0/M0) between January 1998 and June 2016 who underwent RP from the South Australian Prostate Cancer Clinical Outcomes Collaborative database. Factors associated with risk of PSMs were identified using Poisson regression. The impact of PSMs on clinical outcomes (BCR, second treatment, and PCSM) was assessed using competing risk regression. Results: Of the 2827 eligible participants, 28% had PSMs-10% apical, 6% bladder neck, 17% posterolateral, and 5% at multiple locations. Median follow-up was 9.6 years with 81 deaths from prostate cancer recorded. Likelihood of PSM increased with higher pathological grade and pathological tumor stage, and greater tumour volume, but decreased with increasing surgeon volume (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.88-0.98, per 100 previous prostatectomies). PSMs were associated with increased risk of BCR (adjusted sub-distribution hazard ratio [sHR] 2.5; 95% CI 2.1-3.1) and second treatment (sHR 2.9; 95% CI 2.4-3.5). Risk of BCR was increased similarly for each PSM location, but was higher for multiple margin sites. We found no association between PSMs and PCSM. Conclusion: Our findings support previous research suggesting that PSMs are not independently associated with PCSM despite strong association with BCR. Reducing PSM rates remains an important objective, given the higher likelihood of secondary treatment with associated comorbidities.

A micro-randomized pilot study to examine the impact of just-in-time nudging on after-dinner snacking in adults with type 2 diabetes: A study protocol.

AIM: To determine whether a digital nudge soon after dinner reduces after-dinner snacking events as measured objectively by continuous glucose monitoring (CGM) in patients with type 2 diabetes (T2D). METHODS: This is a single-site micro-randomized trial (MRT). People with T2D, aged 18-75 years, managed with diet or a stable dose of oral antidiabetic medications for at least 3 months, and who habitual snack after dinner at least 3 nights per week, will be recruited. Picto-graphic nudges were designed by mixed research methods. After a 2-week lead-in phase to determine eligibility and snacking behaviours by a CGM detection algorithm developed by the investigators, participants will be micro-randomized daily (1:1) to a second 2-week period to either a picto-graphic nudge delivered-in-time (Intui Research) or no nudge. During lead-in and MRT phases, 24-hour glucose will be measured by CGM, sleep will be tracked by an under-mattress sleep sensor, and dinner timing will be captured daily by photographing the evening meal. RESULTS: The primary outcome is the difference in the incremental area under the CGM curve between nudging and non-nudging days during the period from 90 minutes after dinner until 04:00 AM. Secondary outcomes include the effect of baseline characteristics on treatment, and comparisons of glucose peaks and time-in-range between nudging and non-nudging days. The feasibility of 'just-in-time' messaging and nudge acceptability will be evaluated, along with the analysis of sleep quality measures and their night-to-night variability. CONCLUSIONS: This study will provide preliminary evidence of the impact of appropriately timed digital nudges on 24 -hour intertitial glucose levels resulting from altered after-dinner snacking in people with T2D. An exploratory sleep substudy will provide evidence of a bidirectional relationship between after-dinner snacking behaviour, glycaemia and sleep. Ultimately, this study will allow for the design of a future confirmatory study of the potential for digital nudging to improve health related behaviours and health outcomes.

Intermittent fasting plus early time-restricted eating versus calorie restriction and standard care in adults at risk of type 2 diabetes: a randomized controlled trial.

Intermittent fasting appears an equivalent alternative to calorie restriction (CR) to improve health in humans. However, few trials have considered applying meal timing during the 'fasting' day, which may be a limitation. We developed a novel intermittent fasting plus early time-restricted eating (iTRE) approach. Adults (N = 209, 58 ± 10 years, 34.8 ± 4.7 kg m-2) at increased risk of developing type 2 diabetes were randomized to one of three groups (2:2:1): iTRE (30% energy requirements between 0800 and 1200 hours and followed by a 20-h fasting period on three nonconsecutive days per week, and ad libitum eating on other days); CR (70% of energy requirements daily, without time prescription); or standard care (weight loss booklet). This open-label, parallel group, three-arm randomized controlled trial provided nutritional support to participants in the iTRE and CR arms for 6 months, with an additional 12-month follow-up. The primary outcome was change in glucose area under the curve in response to a mixed-meal tolerance test at month 6 in iTRE versus CR. Glucose tolerance was improved to a greater extent in iTRE compared with CR (-10.10 (95% confidence interval -14.08, -6.11) versus -3.57 (95% confidence interval -7.72, 0.57) mg dl-1 min-1; P = 0.03) at month 6, but these differences were lost at month 18. Adverse events were transient and generally mild. Reports of fatigue were higher in iTRE versus CR and standard care, whereas reports of constipation and headache were higher in iTRE and CR versus standard care. In conclusion, incorporating advice for meal timing with prolonged fasting led to greater improvements in postprandial glucose metabolism in adults at increased risk of developing type 2 diabetes. ClinicalTrials.gov identifier NCT03689608 .

Graft choices for paediatric anterior cruciate ligament reconstruction: State of the art.

The paediatric population is at particularly high risk for anterior cruciate ligament (ACL) injuries due to high rates of sports participation. Other risk factors for ACL injuries in children include but are not limited to being female, generalised ligamentous laxity, a high body mass index (BMI), and poor neuromuscular control. ACL reconstruction (ACLR) is commonly done to treat ACL injuries and allow for return to sports and daily activities. ACL repair is another option with ongoing techniques being developed. The high rates of graft failure in children reported in recent publications on ACL repair are very concerning. Special consideration must be taken in ACLR in the skeletally immature patient due to the risk of growth-related complications, such as limb deformity or growth arrest, that can arise from drilling across or disrupting the physis. Graft choices for paediatric ACLR include iliotibial band (ITB) over the top and over the front, hamstring autograft, bone patellar tendon bone (BTB) autograft, quadriceps tendon autograft, and allograft. Factors for each graft choice to consider include graft size, graft failure rates, donor site morbidity, requirement for bony tunnels, the post-op rehabilitation process, and return to sport outcomes. Each graft has its benefits and disadvantages for the individual patient, depending on age, skeletal maturity, and goals for recovery. Lateral extra-articular tenodesis (LET) is another option to consider with paediatric ACLR because LET has been shown to decrease the re-rupture rate in adult ACLR. After surgery, patient follow-up until at least the growth plates are closed is important. This article aims to provide an overview and comparison of the various graft types to aid in the graft choice decision making process for paediatric ACLR.

A Self-Help Online Intervention Is Associated with Reduced Distress and Improved Mental Wellbeing in Australian Farmers: The Evaluation and Key Mechanisms of www.ifarmwell.com.au.

OBJECTIVES: Farmers are faced with many stressors, along with numerous barriers to accessing traditional forms of mental health support. The ifarmwell online intervention was co-designed with farmers and is informed by Acceptance and Commitment Therapy to equip farmers with transferable coping strategies, particularly to help them cope with circumstances beyond their control. We aimed to evaluate the effect of ifarmwell on farmers' short- and long-term distress and mental wellbeing. METHODS: Australian farmers (21-73 years) who registered on www.ifarmwell.com.au completed measures at the commencement of module 1 (N = 228), the end of the intervention (N = 77) and 6-months post-intervention (N = 61). Primary outcomes included distress (Kessler Psychological Distress Scale) and mental wellbeing (Mental Health Continuum - Short Form). We also examined the relationship between distress, mental wellbeing, neuroticism (Quickscales-R) and ACT-based psychological mechanisms; psychological inflexibility (Acceptance and Action Questionnaire-II), cognitive fusion (Cognitive Fusion Questionnaire), believability of automatic thoughts (Automatic Thoughts Questionnaire-B), coping via acceptance (4 items from the situational COPE) and mindfulness (Five Facet Mindfulness Questionnaire-Short Form). Secondary outcomes of acceptability (Client Satisfaction Questionnaire-8) and usability (System Usability Scale) were also explored. RESULTS: Pre- to post-intervention, farmers' distress decreased and mental wellbeing increased. These effects were maintained at 6-month follow-up. Changes in these outcomes were greatest for participants who entered the intervention with high baseline distress (߈= -0.59, 95%CI =[-0.70, -0.47]) and low mental wellbeing (߈= -0.33, 95%CI = [-0.47, -0.19]). Decreases in distress and increases in mental wellbeing were associated with decreases in psychological inflexibility, cognitive fusion, and believability of thoughts, and increases in coping via acceptance and mindfulness. Levels of satisfaction (M = 26.92/32) and usability (M = 84.70/100) were high, and 94.6% of participants said they would recommend ifarmwell to a friend in need of similar advice and tools. CONCLUSIONS: ifarmwell is an effective and usable intervention that is likely to help farmers reduce their levels of distress and improve their mental wellbeing, by improving their psychological flexibility, ability to focus on the present and accept things beyond their control, as well as by reducing the extent to which they believe unhelpful thoughts.

Time-restricted eating alters the 24-hour profile of adipose tissue transcriptome in men with obesity.

OBJECTIVE: Time-restricted eating (TRE) restores circadian rhythms in mice, but the evidence to support this in humans is limited. The objective of this study was to investigate the effects of TRE on 24-hour profiles of plasma metabolites, glucoregulatory hormones, and the subcutaneous adipose tissue (SAT) transcriptome in humans. METHODS: Men (n = 15, age = 63 [4] years, BMI 30.5 [2.4] kg/m2 ) were recruited. A 35-hour metabolic ward stay was conducted at baseline and after 8 weeks of 10-hour TRE. Assessment included 24-hour profiles of plasma glucose, nonesterified fatty acid (NEFA), triglyceride, glucoregulatory hormones, and the SAT transcriptome. Dim light melatonin onset and cortisol area under the curve were calculated. RESULTS: TRE did not alter dim light melatonin onset but reduced morning cortisol area under the curve. TRE altered 24-hour profiles of insulin, NEFA, triglyceride, and glucose-dependent insulinotropic peptide and increased transcripts of circadian locomotor output cycles protein kaput (CLOCK) and nuclear receptor subfamily 1 group D member 2 (NR1D2) and decreased period circadian regulator 1 (PER1) and nuclear receptor subfamily 1 group D member 1 (NR1D1) at 12:00 am. The rhythmicity of 450 genes was altered by TRE, which enriched in transcripts for transcription corepressor activity, DNA-binding transcription factor binding, regulation of chromatin organization, and small GTPase binding pathways. Weighted gene coexpression network analysis revealed eigengenes that were correlated with BMI, insulin, and NEFA. CONCLUSIONS: TRE restored 24-hour profiles in hormones, metabolites, and genes controlling transcriptional regulation in SAT, which could underpin its metabolic health benefit.

Exploring the Interplay Between Message Format, Need for Cognition and Personal Relevance on Processing Messages About Physical Activity: a Two-Arm Randomized Experimental Trial.

BACKGROUND: According to the Elaboration Likelihood Model, persuasion can occur via two different routes (the central route and peripheral route), with the route utilized dependent on factors associated with motivation and ability. This study aimed to explore the moderating role of need for cognition (NFC) and perceived relevance on the processing of physical activity messages designed to persuade via either the central route or the peripheral route. METHOD: Participants (N = 50) were randomized to receive messages optimized for central route processing or messages optimized for peripheral route processing. Eye-tracking devices were used to assess attention, which was the primary outcome. Message perceptions and the extent of persuasion (changes in physical activity determinants) were also assessed via self-report as secondary outcomes. Moderator effects were examined using interaction terms within mixed effects models and linear regression models. RESULTS: There were no detected interactions between condition and NFC for any of the study outcomes (all ps > .05). Main effects of personal relevance were observed for some self-report outcomes, with increased relevance associated with better processing outcomes. An interaction between need for cognition and personal relevance was observed for perceived behavioral control (p = 0.002); greater relevance was associated with greater perceived behavioral control for those with a higher need for cognition. CONCLUSION: Matching physical activity messages based on NFC may not increase intervention efficacy. Relevance of materials is associated with greater change in physical activity determinants and may be more so among those with a higher NFC.

Impact of different unconditional monetary incentives on survey response rates in men with prostate cancer: a 2-arm randomised trial.

BACKGROUND: Men are often viewed as a difficult group to recruit for psychological research, including in psycho-oncology. Whilst research has demonstrated the effectiveness of small monetary incentives for encouraging research participation, little research has examined different large unconditional incentive amounts. Larger unconditional incentives may result in increased participation of men in psychological research. This randomised study within a case-control trial of men diagnosed with early-stage prostate cancer aimed to investigate whether (a) response rates to a 30-min questionnaire completed via mail, online, or phone would vary with different unconditional incentive amounts, and (b) demographics would vary in those who responded within the different incentive groups. METHODS: We conducted this randomised study within a case-control cross-sectional study aiming to identify the social-ecological factors influencing treatment discontinuation in prostate cancer patients. A total of 238 participants from the cross-sectional study were randomised to receive one of two unconditional incentives (n = 121 received AUD$10, n = 117 received AUD$20) with the study materials (consent form and survey). RESULTS: Overall, 113 (47%) responded; n = 61/121 (50.4%) in the AUD$10 group, and n = 52/117 (44.4%) in the AUD$20 group. No evidence of a difference was found in response rates by incentive group (odds ratio 1.27, 95% CI = 0.76-2.12, p = 0.36). Additionally, there were no evident differences in the demographics of the responders vs. non-responders within each incentive group (all p > 0.05). CONCLUSIONS: Unlike previous research, we were unable to show that higher monetary incentives were more effective for increasing response rates. An AUD$20 unconditional incentive may be no more effective than a lesser amount for encouraging prostate cancer survivors to participate in research involving long questionnaires. Future research should consider the cost-benefits of providing large unconditional incentives, as non-responses will result in lost resources perhaps better utilised in other engagement strategies.

Krill oil improved osteoarthritic knee pain in adults with mild to moderate knee osteoarthritis: a 6-month multicenter, randomized, double-blind, placebo-controlled trial.

BACKGROUND: Osteoarthritis (OA) is a major cause of chronic pain and disability worldwide. Treatment generally focuses on symptom relief through nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics, which may incur side effects. Krill oil, rich in anti-inflammatory long-chain (LC) omega-3 ( ω-3) PUFAs and astaxanthin, may be a safe and effective alternative treatment. OBJECTIVES: This study sought to investigate the effects of a commercially available krill oil supplement on knee pain in adults with mild to moderate knee OA. Secondary outcomes were knee stiffness; physical function; NSAID use; Omega-3 Index; and lipid, inflammatory, and safety markers. METHODS: Healthy adults (n = 235, 40-65 y old, BMI >18.5 to <35 kg/m2), clinically diagnosed with mild to moderate knee OA, regular knee pain, and consuming <0.5 g/d LC ω-3 PUFAs, participated in a 6-mo double-blind, randomized, placebo-controlled, multicenter trial. Participants consumed either 4 g krill oil/d (0.60 g EPA/d, 0.28 g DHA/d, 0.45 g astaxanthin/d) or placebo (mixed vegetable oil). Knee outcomes were assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) numeric scale (normalized to scores of 0-100). Outcomes were assessed at baseline, 3 mo, and 6 mo. RESULTS: Omega-3 Index increased with the krill oil supplement compared with placebo (from 6.0% to 8.9% compared with from 5.5% to 5.4%, P < 0.001). Knee pain score improved in both groups with greater improvements for krill oil than for placebo (difference in adjusted mean change between groups at 6 mo: -5.18; 95% CI: -10.0, -0.32; P = 0.04). Knee stiffness and physical function also had greater improvements with krill oil than with placebo (difference in adjusted mean change between groups at 6 mo: -6.45; 95% CI: -12.1, -0.9 and -4.67; 95% CI: -9.26, -0.05, respectively; P < 0.05). NSAID use, serum lipids, and inflammatory and safety markers did not differ between groups. CONCLUSIONS: Krill oil was safe to consume and resulted in modest improvements in knee pain, stiffness, and physical function in adults with mild to moderate knee OA.This trial was registered at clinicaltrials.gov as NCT03483090.

Why do men with prostate cancer discontinue active surveillance for definitive treatment? A mixed methods investigation.

OBJECTIVES: To explore the personal and/or medical reasons patients on active surveillance (AS) have, or consider having, further definitive treatment for their prostate cancer. Research suggests up to 50% of patients on AS will discontinue within 5 years, though reasons for discontinuation from the patient's perspective is under-explored. METHODS: Prostate cancer patients who were or had been on AS for at least 6 months were recruited. A questionnaire assessed reasons for receiving/considering definitive treatment and the extent to which reasons were personal or medical. Clinical information was extracted from a state-level population registry. A subset of participants were interviewed to further explore questionnaire responses. RESULTS: One-hundred and-three individuals completed the survey; 33 were also interviewed. Fifty-four survey participants (52%) had discontinued AS for definitive treatment. Common reasons for discontinuation were evidence of disease progression, doctor recommendation, desire to act, and fear of progression. Many participants who considered or had treatment reported weighing medical and personal factors equally in their decision. Interview participants described strongly considering any amount of disease progression and personal factors such as fear of progression, family concerns, and adverse vicarious experiences when deciding whether to pursue treatment. CONCLUSION: Both medical and personal factors are considered when deciding whether to discontinue AS. Identifying predictors of discontinuation is essential for informing supportive care services to improve AS management.

Harnessing the Heterogeneity of Prostate Cancer for Target Discovery Using Patient-Derived Explants.

Prostate cancer is a complex and heterogeneous disease, but a small number of cell lines have dominated basic prostate cancer research, representing a major obstacle in the field of drug and biomarker discovery. A growing lack of confidence in cell lines has seen a shift toward more sophisticated pre-clinical cancer models that incorporate patient-derived tumors as xenografts or explants, to more accurately reflect clinical disease. Not only do these models retain critical features of the original tumor, and account for the molecular diversity and cellular heterogeneity of prostate cancer, but they provide a unique opportunity to conduct research in matched tumor samples. The challenge that accompanies these complex tissue models is increased complexity of analysis. With over 10 years of experience working with patient-derived explants (PDEs) of prostate cancer, this study provides guidance on the PDE method, its limitations, and considerations for addressing the heterogeneity of prostate cancer PDEs that are based on statistical modeling. Using inhibitors of the molecular chaperone heat shock protein 90 (Hsp90) as an example of a drug that induces robust proliferative response, we demonstrate how multi-omics analysis in prostate cancer PDEs is both feasible and essential for identification of key biological pathways, with significant potential for novel drug target and biomarker discovery.

Evaluation of selective bone scan staging in prostate cancer - external validation of current strategies and decision-curve analysis.

BACKGROUND: Recommendations for staging newly diagnosed prostate cancer patients vary between guidelines and literature. METHODS: Our objective was to validate and compare prediction models selecting newly diagnosed prostate cancer patients for bone scan staging. To achieve this, we validated eleven models in a population-based cohort of 10,721 patients diagnosed with prostate cancer between 2005 and 2019. The primary outcome was net-benefit. This was assessed at different balances of conservatism and tolerance, represented by preference ratio and number-willing-to-test (NWT). Secondary outcomes included calibration slope, calibration-in-the-large (intercept), and discrimination measured by Area-under-the-receiver-operator-characteristics curve (AUC). RESULTS: For preference ratios less than 1:39 (NWT greater than 40), scanning everyone provided greater net-benefit than selective staging. For preference ratios 1:39 to 3:97 (NWT 33-40), the European Association of Urology (EAU) 2020 guideline recommendation was the best approach. For preference ratios 3:97-7:93 (NWT 14-33), scanning EAU high-risk patients only was preferable. For preference ratios 7:93-1:9 (NWT 10-13), scanning only Gnanapragasam Group 5 patients was best. All models had similar fair discrimination (AUCs 0.68-0.80), but most had poor calibration. CONCLUSIONS: We identified three selective staging strategies that outperformed all other approaches but did so over different ranges of conservatism and tolerance. Scanning only EAU high-risk patients provided the greatest net-benefit over the greatest range of preference ratios and scenarios, but other options may be preferable depending upon the local healthcare system's degree of conservatism and tolerance.

In Situ Simulation for Adoption of New Technology to Improve Sepsis Care in Rural Emergency Departments.

OBJECTIVES: The aims of the study were to evaluate whether in situ (on-site) simulation training is associated with increased telemedicine use for patients presenting to rural emergency departments (EDs) with severe sepsis and septic shock and to evaluate the association between simulation training and telehealth with acute sepsis bundle (SEP-1) compliance and mortality. METHODS: This was a quasi-experimental study of patients presenting to 2 rural EDs with severe sepsis and/or septic shock before and after rollout of in situ simulation training that included education on sepsis management and the use of telehealth. Unadjusted and adjusted analyses were conducted to describe the association of simulation training with sepsis process of care markers and with mortality. RESULTS: The study included 1753 patients, from 2 rural EDs, 629 presented before training and 1124 presented after training. There were no differences in patient characteristics between the 2 groups. Compliance with several SEP-1 bundle components improved after training: antibiotics within 3 hours, intravenous fluid administration, repeat lactic acid assessment, and vasopressor administration. The use of telemedicine increased from 2% to 5% after training. Use of telemedicine was associated with increases in repeat lactic acid assessment and reassessment for septic shock. We did not demonstrate an improvement in mortality across either of the 2 group comparisons. CONCLUSIONS: We demonstrate an association between simulation and improved care delivery. Implementing an in situ simulation curriculum in rural EDs was associated with a small increase in the use of telemedicine and improvements in sepsis process of care markers but did not demonstrate improvement in mortality. The small increase in telemedicine limited conclusions on its impact.

Combining Farmers' Preferences With Evidence-Based Strategies to Prevent and Lower Farmers' Distress: Co-design and Acceptability Testing of ifarmwell.

BACKGROUND: Farming is physically and psychologically hazardous. Farmers face many barriers to help seeking from traditional physical and mental health services; however, improved internet access now provides promising avenues for offering support. OBJECTIVE: This study aims to co-design with farmers the content and functionality of a website that helps them adopt transferable coping strategies and test its acceptability in the broader farming population. METHODS: Research evidence and expert opinions were synthesized to inform key design principles. A total of 18 farmers detailed what they would like from this type of website. Intervention logic and relevant evidence-based strategies were mapped. Website content was drafted and reviewed by 2 independent mental health professionals. A total of 9 farmers provided detailed qualitative feedback on the face validity of the draft content. Subsequently, 9 farmers provided feedback on the website prototype. Following amendments and internal prototype testing and optimization, prototype usability (ie, completion rate) was examined with 157 registered website users who were (105/157, 66.9%) female, aged 21-73 years; 95.5% (149/156) residing in inner regional to very remote Australia, and 68.2% (107/157) "sheep, cattle and/or grain farmers." Acceptability was examined with a subset of 114 users who rated at least module 1. Interviews with 108 farmers who did not complete all 5 modules helped determine why, and detailed interviews were conducted with 18 purposively sampled users. Updates were then made according to adaptive trial design methodology. RESULTS: This systematic co-design process resulted in a web-based resource based on acceptance and commitment therapy and designed to overcome barriers to engagement with traditional mental health and well-being strategies-ifarmwell. It was considered an accessible and confidential source of practical and relevant farmer-focused self-help strategies. These strategies were delivered via 5 interactive modules that include written, drawn, and audio- and video-based psychoeducation and exercises, as well as farming-related jokes, metaphors, examples, and imagery. Module 1 included distress screening and information on how to speak to general practitioners about mental health-related concerns (including a personalized conversation script). Modules were completed fortnightly. SMS text messages offered personalized support and reminders. Qualitative interviews and star ratings demonstrated high module acceptability (average 4.06/5 rating) and suggested that additional reminders, higher quality audio recordings, and shorter modules would be useful. Approximately 37.1% (52/140) of users who started module 1 completed all modules, with too busy or not got to it yet being the main reason for non-completion, and previous module acceptability not predicting subsequent module completion. CONCLUSIONS: Sequential integration of research evidence, expert knowledge, and farmers' preferences in the co-design process allowed for the development of a self-help intervention that focused on important intervention targets and was acceptable to this difficult-to-engage group. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12617000506392; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372526.

Eating architecture in adults at increased risk of type 2 diabetes: associations with body fat and glycaemic control.

Eating architecture is a term that describes meal frequency, meal timing and meal size and the daily variation in each of these. The aim of this study was to determine the relationship between components of eating architecture on body fat and markers of glycaemic control in healthy adults at increased risk of type 2 diabetes (T2DM). Participants (n 73, 39 males, age 58·8 (8·1) years, BMI 33·4 (4·4) kg/m2) recorded food intake and wore accelerometers and continuous glucose monitors (CGM) for 7-14 d under free-living conditions. Body fat and glycated Hb (HbA1c) were also measured. The mean and day-to-day variation (calculated as the standard deviation during the monitoring period) of each component of eating architecture were calculated. Multivariable linear regression models were constructed for three separate outcome variables (body fat mass, mean CGM glucose and HbA1c) for each component of eating architecture before and after adjustment for confounders. Higher variability in the time of first meal consumption was associated with increased body fat mass after adjusting for confounders (ß = 0·227, 95 % CI: 0·019, 0·434, P = 0·033). Increased variability in the time lag from waking to first meal consumption was also positively associated with increased HbA1c after adjustment (ß = 0·285, 95 % CI: 0·040, 0·530, P = 0·023). Low day-to-day variability in first meal consumption was associated with lower body fat and improved glucose control in adults at increased risk of T2DM. Routine consumption of meals may optimise temporal regulation to anticipate and respond appropriately to a glucose challenge.

Acceptability and Preliminary Efficacy of a Web- and Telephone-Based Personalised Exercise Intervention for Individuals with Metastatic Prostate Cancer: The ExerciseGuide Pilot Randomised Controlled Trial.

Preliminary research has shown the effectiveness of supervised exercise-based interventions in alleviating sequela resulting from metastatic prostate cancer. However, many individuals encounter barriers that limit the uptake of face-to-face exercise. Technology-enabled interventions offer a distance-based alternative. This pilot study aimed to explore the acceptability, safety and preliminary efficacy of a web-based exercise intervention (ExerciseGuide) in individuals with metastatic prostate cancer. Forty participants (70.2 ± 8.5 years) with metastatic prostate cancer were randomised into the 8-week intervention (N = 20) or a wait-list control (N = 20). The intervention arm had access to a computer-tailored website, personalised exercise prescription and remote supervision. ExerciseGuide was deemed acceptable with a score ≥20 on the client satisfaction questionnaire; however, the usability score was just below the pre-specified score of ≥68 on the software usability scale. There were no serious adverse events reported. Moderate-to-vigorous physical activity levels between baseline and follow-ups were significantly higher (10.0 min per day; 95% CI = (1.3-18.6); p = 0.01) in the intervention group compared to wait-list control. There were also greater improvements in step count (1332; 95% CI = (159-2505); p = 0.02) and identified motivation (0.4, 95% CI = (0.0, 0.7); p = 0.04). Our findings provide preliminary evidence that ExerciseGuide is acceptable, safe and efficacious among individuals with metastatic prostate cancer.