Quantification of the effect of in utero events on lifetime resilience in dairy cows.

Currently, the dairy industry is facing many challenges that could affect its sustainability, including climate change and public perception of the industry. As a result, interest is increasing in the concept of identifying resilient animals, those with a long productive lifespan, as well as good reproductive performance and milk yield. There is much evidence that events in utero, that is, the developmental origins of health and disease hypothesis, alter the life-course health of offspring and we hypothesized that these could alter resilience in calves, where resilience is identified using lifetime data. The aim of this study was to quantify lifetime resilience scores (LRS) using an existing scoring system, based on longevity with secondary corrections for age at first calving and calving interval, and to quantify the effects of in utero events on the LRS using 2 datasets. The first was a large dataset of cattle on 83 farms in Great Britain born from 2006 to 2015 and the second was a smaller, more granular dataset of cattle born between 2003 and 2015 in the Langhill research herd at Scotland's Rural College. Events during dam's pregnancy included health events (lameness, mastitis, use of an antibiotic or anti-inflammatory medication), the effect of heat stress as measured by temperature-humidity index, and perturbations in milk yield and quality (somatic cell count, percentage fat, percentage protein and fat:protein ratio). Daughters born to dams that experienced higher temperature-humidity indexes while they were in utero during the first and third trimesters of pregnancy had lower LRS. Daughter LRS were also lower where milk yields or median fat percentages in the first trimester were low, and when milk yields were high in the third trimester. Dam LRS was positively associated with LRS of their offspring; however, as parity of the dam increased, LRS of their calves decreased. Similarly, in the Langhill herd, dams of a higher parity produced calves with lower LRS. Additionally, dams that recorded a high maximum locomotion score in the third trimester of pregnancy were negatively associated with lower calf LRS in the Langhill herd. Our results suggest that events that occur during pregnancy have lifelong consequences for the calf's lifetime performance. However, experience of higher temperature-humidity indexes, higher dam LRS, and mothers in higher parities explained a relatively small proportion of variation in offspring LRS, which suggests that other factors play a substantial role in determining calf LRS. Although "big data" can contain a considerable amount of noise, similar findings between the 2 datasets indicate it is likely these findings are real.

Reducing Systematic Uncertainty in Computed Redox Potentials for Aqueous Transition-Metal-Substituted Polyoxotungstates.

Polyoxometalates have attracted significant interest owing to their structural diversity, redox stability, and functionality at the nanoscale. In this work, density functional theory calculations have been employed to systematically study the accuracy of various exchange-correlation functionals in reproducing experimental redox potentials, U0Red in [PW11M(H2O)O39]q- M = Mn(III/II), Fe(III/II), Co(III/II), and Ru(III/II). U0Red calculations for [PW11M(H2O)O39]q- were calculated using a conductor-like screening model to neutralize the charge in the cluster. We explicitly located K+ counterions which induced positive shifting of potentials by > 500 mV. This approximation improved the reproduction of redox potentials for Kx[XW11M(H2O)O39]q-x M = Mn(III/II)/Co(III/II). However, uncertainties in U0Red for Kx[PW11M(H2O)O39]q-x M = Fe(III/II)/Ru(III/II) were observed because of the over-stabilization of the ion-pairs. Hybrid functionals exceeding 25% Hartree-Fock exchange are not recommended because of large uncertainties in ΔU0Red attributed to exaggerated proximity of the ion-pairs. Our results emphasize that understanding the nature of the electrode and electrolyte environment is essential to obtain a reasonable agreement between theoretical and experimental results.

Underestimation of Per- and Polyfluoroalkyl Substances in Biosolids: Precursor Transformation During Conventional Treatment.

Wastewater treatment plants generate a solid waste known as biosolids. The most common management option for biosolids is to beneficially reuse them as an agricultural amendment, but because of the risk of pathogen exposure, many regulatory bodies require pathogen reduction before biosolids reuse. Per- and polyfluoroalkyl substances (PFAS) are well documented in biosolids, but limited information is available on how biosolids treatment processes impact PFAS. Furthermore, quantification of PFAS has focused on perfluoroalkyl acids (PFAAs) which are a small fraction of thousands of PFAS known to exist. The objective of this study was to quantify 92 PFAS in biosolids collected from eight biosolids treatment facilities before and after four pathogen treatment applications: composting, heat treatment, lime treatment, and anaerobic digestion. Overall, total PFAS concentrations before and after treatment were dominated by PFAA precursor species, in particular, diPAPs which accounted for a majority of the mass of the Σ92PFAS. This differs from historic data that found PFAAs, primarily PFOS, to dominate total PFAS concentrations. Treatment options such as heat treatment and composting changed the ratio of PFAA precursors to PFAAs indicating a transformation of PFAS during treatment. This study finds that PFAA precursors are likely underrepresented by other studies and make up a larger percentage of the total PFAS concentration in biosolids than previously estimated.

Supportive care needs in Australian melanoma patients and caregivers: results from a quantitative cross-sectional survey.

PURPOSE: This study aimed to investigate the supportive care needs of Australian melanoma patients and their caregivers to form the basis for improving services. METHODS: General and melanoma-related supportive care needs in melanoma patients were measured using the SCNS-SF34 and SCNS-M12 respectively, whereas caregivers completed the SCNS-P&C. Patients also completed the MCQ-28 and FCRI-9, with all participants completing the QLQ-C30, DASS-21, and questions measuring utilisation and preference for supportive health services. Multivariable stepwise logistic regression was used to identify variables associated with unmet needs in melanoma patients. RESULTS: A total of 56 early-stage patients, 100 advanced-stage patients, and 37 caregivers participated. At least three-quarters ([Formula: see text] 75%) of each participant group reported at least one unmet need. Of the ten most reported unmet needs in each participant group, at least six ([Formula: see text] 60%) were related to psychological and emotional well-being, with access to a psychologist the most desired service (> 25%). Fear of cancer recurrence was equally prevalent in both patient groups at a level indicative of need for intervention. Advanced-stage patients reported significantly (p < 0.05) more unmet psychological, physical and daily living, and sexuality needs, and significantly (p < 0.05) worse functioning than early-stage patients. CONCLUSION: Australian melanoma patients and caregivers report substantial unmet supportive care needs, particularly regarding their psychological and emotional well-being. Psychological and emotional well-being services, such as access to a clinical psychologist or implementation of patient-reported outcome measures, should be incorporated into routine melanoma care to address unmet patient and caregiver needs and improve well-being.

Predicting lameness in dairy cattle using untargeted liquid chromatography-mass spectrometry-based metabolomics and machine learning.

Lameness in dairy cattle is a highly prevalent condition that impacts on the health and welfare of dairy cows. Prompt detection and implementation of effective treatment is important for managing lameness. However, major limitations are associated with visual assessment of lameness, which is the most commonly used method to detect lameness. The aims of this study were to investigate the use of metabolomics and machine learning to develop novel methods to detect lameness. Untargeted metabolomics using liquid chromatography-mass spectrometry (LC-MS) alongside machine learning models and a stability selection method were utilized to evaluate the predictive accuracy of differences in the metabolomics profile of first-lactation dairy cows before (during the transition period) and at the time of lameness (based on visual assessment using the 0-3 scale of the Agriculture and Horticulture Development Board). Urine samples were collected from 2 cohorts of dairy heifers and stored at -86°C before analysis using LC-MS. Cohort 1 (n = 90) cows were recruited as current first-lactation cows with weekly mobility scores recorded over a 4-mo timeframe, from which newly lame and nonlame cows were identified. Cohort 2 (n = 30) cows were recruited within 3 wk before calving, and lameness events (based on mobility score) were recorded through lactation until a minimum of 70 d in milk (DIM). All cows were matched paired by DIM ± 14 d. The median DIM at lameness identification was 187.5 and 28.5 for cohort 1 and 2, respectively. The best performing machine learning models predicted lameness at the time of lameness with an accuracy of between 81 and 82%. Using stability selection, the prediction accuracy at the time of lameness was 80 to 81%. For samples collected before and after calving, the best performing machine learning model predicted lameness with an accuracy of 71 and 75%, respectively. The findings from this study demonstrate that untargeted LC-MS profiling combined with machine learning methods can be used to predict lameness as early as before calving and before observable changes in gait in first-lactation dairy cows. The methods also provide accuracies for detecting lameness at the time of observable changes in gait of up to 82%. The findings demonstrate that these methods could provide substantial advancements in the early prediction and prevention of lameness risk. Further external validation work is required to confirm these findings are generalizable; however, this study provides the basis from which future work can be conducted.

Feasibility, acceptability, and utility of a nurse-led survivorship program for people with metastatic melanoma (MELCARE).

PURPOSE: Immune checkpoint inhibitors (ICIs) and targeted therapy (TT) have improved the survival of people with metastatic melanoma. We assessed the feasibility, acceptability, and utility of a novel model of nurse-led, telehealth-delivered survivorship care (MELCARE) for this survivor group. METHODS: People ≥ 18 years diagnosed with unresectable stage III or stage IV melanoma who were ≥ 6 months post initiation of ICI/TT with a radiological response suggestive of a long-term response to ICI/TT were recruited from a specialist melanoma centre in Australia. All participants received MELCARE, a nurse-led survivorship program involving two telehealth consultations 3 months apart, needs assessment using the Distress Thermometer (DT) and Problem List, and creation of a survivorship care plan. Feasibility, acceptability, and utility were assessed using rates of consent and study completion, time taken to complete each component of MELCARE, the Acceptability of Intervention Measure (AIM), and a customised utility survey. RESULTS: 31/54 (57%) people consented. Participants were male (21, 68%), with a median age of 67 (range: 46-82). Eleven (35%) were receiving/had received ipilimumab and nivolumab and 27 (87%) had ceased treatment. Feasibility was demonstrated with 97% completing MELCARE. Utility was demonstrated on a customised survey and supported by a reduction in the mean DT score (initial: 5.6, SD: 2.9; follow-up: 1.5, SD: 1.2). Acceptability was demonstrated on 3/4 AIM items. CONCLUSION: MELCARE was feasible and acceptable with high levels of utility. However, the consent rate was 57% indicating some people do not require support. Future studies should consider MELCARE's optimal timing, resourcing, and cost-effectiveness.

A cleft lip and palate gene, Irf6, is involved in osteoblast differentiation of craniofacial bone.

BACKGROUND: Interferon regulatory factor 6 (IRF6) plays a critical role in embryonic tissue development, including differentiation of epithelial cells. Besides orofacial clefting due to haploinsufficiency of IRF6, recent human genetic studies indicated that mutations in IRF6 are linked to small mandible and digit abnormalities. The function of IRF6 has been well studied in oral epithelium; however, its role in craniofacial skeletal formation remains unknown. In this study, we investigated the role of Irf6 in craniofacial bone development using comparative analyses between wild-type (WT) and Irf6-null littermate mice. RESULTS: Immunostaining revealed the expression of IRF6 in hypertrophic chondrocytes, osteocytes, and bone matrix of craniofacial tissues. Histological analysis of Irf6-null mice showed a remarkable reduction in the number of lacunae, embedded osteocytes in matrices, and a reduction in mineralization during bone formation. These abnormalities may explain the decreased craniofacial bone density detected by micro-CT, loss of incisors, and mandibular bone abnormality of Irf6-null mice. To validate the autonomous role of IRF6 in bone, extracted primary osteoblasts from calvarial bone of WT and Irf6-null pups showed no effect on osteoblastic viability and proliferation. However, a reduction in mineralization was detected in Irf6-null cells. CONCLUSIONS: Altogether, these findings suggest an autonomous role of Irf6 in regulating bone differentiation and mineralization. Developmental Dynamics 248:221-232, 2019. © 2019 Wiley Periodicals, Inc.

Physical Activity, Tinnitus Severity, and Improved Quality of Life.

OBJECTIVES: The objective of this study was to examine the effects of tinnitus severity on quality of life (QOL) and the benefits physical activity may have on tinnitus severity and QOL. The authors hypothesized that (1) QOL would be negatively correlated with tinnitus severity, (2) physical activity would be negatively correlated with tinnitus severity, (3) tinnitus severity and physical activity would have significant independent effects on QOL, and (4) physical activity would have significant and independent effects on tinnitus severity. DESIGN: An online survey was used to collect data from adults with tinnitus; 1030 individuals initiated the survey. Approximately 40% of responses were not included in data analysis due to incomplete data. The following measures were included in the survey: the Tinnitus Functional Index, the Godin Leisure-Time Exercise Question, the Medical Outcomes Study 36-item short form (Physical Component Score [PCS]; Mental Component Score [MCS]), and the Satisfaction with Life Scale (SWLS). Descriptive statistics, Pearson correlations, and multiple linear regression analyses were conducted. RESULTS: Higher levels of physical activity were significantly associated with improved health-related and global QOL and lower levels of tinnitus severity. Both tinnitus severity (12.3% SWLS, 3.8% PCS, and 21.2% MCS) and physical activity (1.1% SWLS, 5.8% PCS, and 1.1% MCS) accounted for significant unique variations in the QOL measures. Physical activity accounted (0.8% Tinnitus Functional Index) for significant unique variation in tinnitus severity. CONCLUSIONS: Physical activity had a small but statistically significant correlation with QOL and tinnitus distress. Our results suggest that physical activity may be a management strategy for those with tinnitus, but further testing is necessary to assess the relationship between physical activity and tinnitus severity.

Neural Plasticity of Mild Tinnitus: An fMRI Investigation Comparing Those Recently Diagnosed with Tinnitus to Those That Had Tinnitus for a Long Period of Time.

Objectives. The aim of the study was to compare differences in neural correlates of tinnitus in adults with recent onset and others who had the disorder for longer than a year. Design. A total of 25 individuals with tinnitus were divided into groups based on the amount of time for which they had experienced tinnitus: <1 year (RTIN) or >1 year (LTIN). Subjects underwent an fMRI scan while listening to affective sounds from the International Affective Digital Sounds database. Resting state functional connectivity data were also collected. Results. The RTIN group recruited the posterior cingulate and insula to a greater extent than the LTIN group when processing affective sounds. In addition, we found that the LTIN group engaged more frontal regions when listening to the stimuli compared to the RTIN group. Lastly, we found increased correlations between the default mode network and the precuneus in RTIN patients compared to LTIN at rest. Conclusion. Our results suggest that the posterior cingulate and insula may be associated with an early emotional reaction to tinnitus in both task and resting states. Over time, tinnitus patients may recruit more frontal regions to better control their emotional response and exhibit altered connectivity in the default mode network.

Computation of 31P NMR chemical shifts in Keggin-based lacunary polyoxotungstates.

Density Functional Theory (DFT) calculations were employed to systematically study the accuracy of various exchange-correlation functionals in reproducing experimental 31P NMR chemical shifts, δExp(31P) for Keggin, [PW12O40]3- and corresponding lacunary clusters: [PW11O39]7-, [A-PW9O34]9-, and [B-PW9O34]9-. Initially, computed chemical shifts, δCalc(31P) were obtained with without neutralising their charge in which associated error, δError(31P), decreased as a function of Hartree-Fock (HF) exchange, attributed to constriction of the P-O tetrahedron. By comparison, δCalc(31P) performed with explicitly located counterions to render the system charge neutral, reduced discrepancies, δError(31P) by 1-2 ppm. However, uncertainties in δCalc(31P) remain, particularly for [B-PW9O34]9- anions attributed to direct electrostatic interactions between the counterions and the central tetrahedron. Optimal results were achieved using the PBE/TZP//PBE0/TZP method, achieving a mean absolute error (MAE) and a mean squared error (MSE) of 4.03 ppm. Our results emphasize that understanding the nature of the electrolyte and solvent environment is essential to obtaining reasonable agreement between theoretical and experimental results.

Per- and polyfluoroalkyl substances (PFAS) in construction and demolition debris (CDD): discerning sources and fate during waste management.

As regulatory frameworks for per- and polyfluoroalkyl substances (PFAS) evolve, the solid waste community seeks to manage PFAS risks effectively. Despite extensive research on PFAS in municipal solid waste (MSW) and wastewater sludge, there is limited information on a major global waste stream which seldom gleans regulatory oversight - construction and demolition debris (CDD). This study sampled a CDD processing facility to provide material-specific information on the PFAS profile within CDD. The bulk CDD accepted by this facility was separated into major categories, representatively sampled, then characterized for total available PFAS (∑92PFAS). As reprocessed CDD is ultimately recycled or landfilled, often unencapsulated or in unlined landfills, the PFAS leaching potential was also examined using two leaching procedures. Among the categories assessed for total PFAS, carpeting, carpet padding, and gypsum drywall showed elevated concentrations compared to other components, with most of the PFAS mass contributed by precursor species. However, materials with the highest total PFAS, such as carpeting, did not necessarily exhibit the highest leaching, and leachate was predominantly composed of terminal species rather than precursors. Extrapolating these findings with national CDD generation and management data inventories suggests that despite MSW having higher total available PFAS concentrations, the leachability of PFAS from landfilled CDD is comparable, raising legitimate concerns with CDD disposal practices, particularly in unlined CDD landfills.

Assessing the suitability of leachability-based screening levels for per- and polyfluoroalkyl substances (PFAS) risk assessment.

In recent years, soil screening levels have been adopted by regulatory agencies for certain per- and polyfluoroalkyl substances (PFAS) to assess the risk of groundwater contamination through leaching. These soil screening levels, determined using an established equilibrium-based partitioning equation, have high variability among regulatory groups largely attributed to the diverse reported partitioning coefficients in the literature. This variability between reported partitioning coefficients, and subsequently soil screening levels, is due to the complex leaching behavior of PFAS not being predicted well by the standard equilibrium-based model. This has led one regulatory group to require batch leaching to assess risk rather than setting default soil screening levels based on partitioning equations. In this work, we conducted leaching experiments on five field-sampled soils impacted by aqueous film-forming foams (AFFF), following Leaching Environmental Assessment Framework (LEAF) Method 1316 and compared the results to expected leaching utilizing an equilibrium-based partitioning equation commonly employed by regulatory agencies to establish soil screening levels. Our analysis found among the six PFAS detected in the soils, which have regulatory leaching thresholds established, the partitioning values assumed by the U.S. EPA exhibited the highest accuracy in predicting leachate concentrations. These partitioning values predicted actual leaching within a ± 20 % margin of error for approximately 50 % of sample points, highlighting limitations in relying solely on equilibrium-based partitioning values as predictors of leaching behavior. This discrepancy between predicted and actual leaching has implications for site managers and regulatory entities overseeing PFAS-contaminated sites, suggesting that soil screening level determinations for PFAS might need to be revised to account for the unique transport characteristics of PFAS.

Neoadjuvant pembrolizumab, dabrafenib and trametinib in BRAFV600-mutant resectable melanoma: the randomized phase 2 NeoTrio trial.

Immune checkpoint inhibitors and BRAF-targeted therapy each improve survival in melanoma. Immune changes early during targeted therapy suggest the mechanisms of each drug class could work synergistically. In the non-comparative, randomized, phase 2 NeoTrio trial, we investigated whether targeted therapy could boost the proportion of patients achieving long-term recurrence-free survival with neoadjuvant immunotherapy in resectable stage III BRAFV600-mutant melanoma. Sixty patients (42% females) were randomized to pembrolizumab alone (n = 20), sequential therapy (dabrafenib plus trametinib followed by pembrolizumab; n = 20) or concurrent (triple) therapy (n = 20), followed by surgery and adjuvant therapy. The primary outcome was pathological response; secondary outcomes included radiographic response, recurrence-free survival, overall survival, surgical outcomes, peripheral blood and tumor analyses and safety. The pathological response rate was 55% (11/20; including six pathological complete responses (pCRs)) with pembrolizumab, 50% (10/20; three pCRs) with sequential therapy and 80% (16/20; ten pCRs) with concurrent therapy, which met the primary outcome in each arm. Treatment-related adverse events affected 75-100% of patients during neoadjuvant treatment, with seven early discontinuations (all in the concurrent arm). At 2 years, event-free survival was 60% with pembrolizumab, 80% with sequential therapy and 71% with concurrent therapy. Recurrences after major pathological response were more common in the targeted therapy arms, suggesting a reduction in response 'quality' when targeted therapy is added to neoadjuvant immunotherapy. Risking the curative potential of immunotherapy in melanoma cannot be justified. Pending longer follow-up, we suggest that immunotherapy and targeted therapy should not be combined in the neoadjuvant setting for melanoma. ClinicalTrials.gov registration: NCT02858921 .

A systematic review with evidence mapping of supportive care interventions for melanoma patients and caregivers.

AIM: We conducted a systematic review and evidence gap mapping to explore the existing supportive care interventions and their impact on well-being outcomes for melanoma patients and caregivers. METHODS: We searched MEDLINE, Embase, Web of Science Index Medicus, CINAHL, Lilacs, CENTRAL (Cochrane Library) and PsycINFO in December 2022, including interventional studies assessing the effectiveness of any supportive care intervention among melanoma patients and/or their caregivers. FINDINGS: Twenty studies were included in this review. These studies consisted of randomised controlled trials (n = 11, 55%), pre-post studies (n = 7, 35%) and quasi-experimental trials (n = 2, 10%). All studies originated from high-income countries and focused primarily on melanoma patients, with no studies identified that focused solely on caregivers. Educational interventions were the most common (n = 7, 35%), followed by psychoeducational interventions (n = 6, 30%) and psychotherapeutic interventions (n = 4, 20%). Nearly all included studies (n = 18, 90%) reported a positive effect of the intervention on the primary outcome of interest; however, most studies (n = 17, 85%) were judged to be at moderate or high risk of bias. Due to heterogeneity of study designs, intervention characteristics and outcome measures, meta-analysis was not conducted. IMPLICATIONS: Supportive care interventions have positive impacts on melanoma patient well-being outcomes, while being acceptable and feasible to conduct. More research is needed regarding supportive care interventions for melanoma caregivers. Future research should focus on eliminating sources of bias through rigorous methodology, with the development of standardised outcome measures for psychosocial outcomes to facilitate future meta-analyses.

The use of machine learning to predict somatic cell count status in dairy cows post-calving.

Udder health remains a priority for the global dairy industry to reduce pain, economic losses, and antibiotic usage. The dry period is a critical time for the prevention of new intra-mammary infections and it provides a point for curing existing intra-mammary infections. Given the wealth of udder health data commonly generated through routine milk recording and the importance of udder health to the productivity and longevity of individual cows, an opportunity exists to extract greater value from cow-level data to undertake risk-based decision-making. The aim of this research was to construct a machine learning model, using routinely collected farm data, to make probabilistic predictions at drying off for an individual cow's risk of a raised somatic cell count (hence intra-mammary infection) post-calving. Anonymized data were obtained as a large convenience sample from 108 UK dairy herds that undertook regular milk recording. The outcome measure evaluated was the presence of a raised somatic cell count in the 30 days post-calving in this observational study. Using a 56-farm training dataset, machine learning analysis was performed using the extreme gradient boosting decision tree algorithm, XGBoost. External validation was undertaken on a separate 28-farm test dataset. Statistical assessment to evaluate model performance using the external dataset returned calibration plots, a Scaled Brier Score of 0.095, and a Mean Absolute Calibration Error of 0.009. Test dataset model calibration performance indicated that the probability of a raised somatic cell count post-calving was well differentiated across probabilities to allow an end user to apply group-level risk decisions. Herd-level new intra-mammary infection rate during the dry period was a key driver of the probability that a cow had a raised SCC post-calving, highlighting the importance of optimizing environmental hygiene conditions. In conclusion, this research has determined that probabilistic classification of the risk of a raised SCC in the 30 days post-calving is achievable with a high degree of certainty, using routinely collected data. These predicted probabilities provide the opportunity for farmers to undertake risk decision-making by grouping cows based on their probabilities and optimizing management strategies for individual cows immediately after calving, according to their likelihood of intra-mammary infection.

Telehealth follow-up consultations for melanoma patients during the COVID-19 pandemic: Patient and clinician satisfaction.

INTRODUCTION: The COVID-19 pandemic caused rapid implementation of telehealth for melanoma follow-up care in Australia. This study explores Australian melanoma patients and clinicians' level of satisfaction with telehealth. METHODS: A cross-sectional study was conducted across three specialist melanoma centres in Sydney, Australia. Melanoma patients (all stages) and clinicians completed mixed methods surveys seeking socio-demographic and clinical information and questionnaires to assess satisfaction with telehealth. Additionally, patients completed measures of quality of life, fear of cancer recurrence and trust in their oncologist. Patients and clinicians provided open-ended responses to qualitative questions about their perceptions of telehealth. RESULTS: One hundred and fifteen patients and 13 clinicians responded to surveys. Telephone was used by 109 (95%) patients and 11 (85%) clinicians. Fifty-seven (50%) patients and nine (69%) clinicians preferred face-to-face consultations, 38 (33%) patients and 3 (23%) clinicians preferred a combination of face-to-face and telehealth consultations. Five (4%) patients and nil clinicians preferred telehealth consultations. Patients diagnosed with early-stage melanoma, using telehealth for the first time, who have lower trust in their oncologist, and having higher care delivery, communication and supportive care concerns were likely to report lower satisfaction with telehealth. Open-ended responses were consistent between patients and clinicians, who reported safety, convenience and improved access to care as major benefits, while identifying personal, interpersonal, clinical and system-related disadvantages. DISCUSSION: While telehealth has been widely implemented during COVID-19, the benefits identified by patients and clinicians may extend past the pandemic. Telehealth may be considered for use in conjunction with face-to-face consultations to provide melanoma follow-up care.

Health-related quality of life in patients with melanoma brain metastases treated with immunotherapy.

Aims: To describe the health-related quality of life (HRQoL) of melanoma brain metastasis (MBM) patients throughout the first 18 weeks of ipilimumab-nivolumab or nivolumab treatment. Materials & methods: HRQoL data (European Organisation for Research and Treatment of Cancer's Core Quality of Life Questionnaire, additional Brain Neoplasm Module, and EuroQol 5-Dimension 5-Level Questionnaire) were collected as a secondary outcome of the Anti-PD1 Brain Collaboration phase II trial. Mixed linear modeling assessed changes over time, whereas the Kaplan-Meier method was used to determine median time to first deterioration. Results: Asymptomatic MBM patients treated with ipilimumab-nivolumab (n = 33) or nivolumab (n = 24) maintained baseline HRQoL. MBM patients with symptoms or leptomeningeal/progressive disease treated with nivolumab (n = 14) reported a statistically significant trend toward improvement. Conclusion: MBM patients treated with either ipilimumab-nivolumab or nivolumab did not report a significant deterioration in HRQoL within 18 weeks of treatment initiation. Clinical trial registration: NCT02374242 (ClinicalTrials.gov).

Historically, people whose melanoma had spread to the brain (known as brain metastases) lived only 4­6 months after diagnosis, with less than 15% alive at 12 months. However, the development of immunotherapies such as nivolumab and ipilimumab to treat advanced melanoma has resulted in more than 50% of patients being alive 5 years after diagnosis. With the effectiveness of these immunotherapies demonstrated in clinical trials, we wanted to examine the impact of these treatments on the health-related quality of life of people with melanoma brain metastases. Using data from a clinical trial evaluating the effectiveness of immunotherapies in people diagnosed with melanoma brain metastases, this study investigated the impact of nivolumab and nivolumab combined with ipilimumab on quality of life. We found that neither nivolumab alone nor nivolumab combined with ipilimumab had a negative effect on quality of life. In summary, this study provides further support for the use of these immunotherapies as first-line treatment for melanoma brain metastases.

Protocol for the implementation of a stepped-care model to address fear of cancer recurrence in patients previously diagnosed with early-stage (0-II) melanoma.

INTRODUCTION: Fear of cancer recurrence (FCR) is commonly reported by patients diagnosed with early-stage (0-II) melanoma and can have a significant impact on daily functioning. This study will pilot the implementation of the Melanoma Care Program, an evidence-based, psychological intervention to reduce FCR, into routine practice, using a stepped-care model. METHODS AND ANALYSIS: Intervention effectiveness and level of implementation will be investigated using a hybrid type I design. Between 4 weeks before and 1 week after their next dermatological appointment, patients with melanoma will be invited to complete the Fear of Cancer Recurrence Inventory Short-Form, measuring self-reported FCR severity. Using a stepped-care model, clinical cut-off points will guide the level of support offered to patients. This includes: (1) usual care, (2) Melanoma: Questions and Answers psychoeducational booklet, and (3) three or five psychotherapeutic telehealth sessions. This longitudinal, mixed-methods pilot implementation study aims to recruit 108 patients previously diagnosed with stage 0-II melanoma. The primary effectiveness outcome is change in FCR severity over time. Secondary effectiveness outcomes include change in anxiety, depression, stress, health-related quality of life and melanoma-related knowledge over time. All outcomes are measured at baseline, within 1 week of the final telehealth session, and 6 and 12 months post-intervention. Implementation stakeholders at each study site and interested patients will provide feedback on intervention acceptability and appropriateness. Implementation stakeholders will also provide feedback on intervention cost, feasibility, fidelity and sustainability. These outcomes will be measured throughout implementation, using questionnaires and semistructured interviews/expert group discussions. Descriptive statistics, linear mixed-effects regression and thematic analysis will be used to analyse study data. ETHICS AND DISSEMINATION: Ethics approval was granted by the Sydney Local Health District-Royal Prince Alfred Zone (2020/ETH02518), protocol number: X20-0495. Results will be disseminated through peer-reviewed journals, conference presentations, social media and result summaries distributed to interested participants. TRIAL REGISTRATION DETAILS: (ACTRN12621000145808).

Embedding electronic patient-reported outcome measures into routine care for patients with stage III MELanoma (ePROMs-MEL): protocol for a prospective, longitudinal, mixed-methods pilot study.

INTRODUCTION: The benefits of patient-reported feedback, using questionnaires that allow patients to report how they feel and function without any interpretation from healthcare professionals, are well established. However, patient-reported outcomes measures (PROMs) are not routinely collected in patients with melanoma in Australia. The aim of this study is to evaluate the feasibility and acceptability of implementing electronic PROMs (ePROMs) into routine care from the perspectives of patients with stage III melanoma and their treating clinical team. METHODS AND ANALYSIS: A minimum of 50 patients and 5 clinicians will be recruited to this prospective, longitudinal pilot study (ePROMs-MELanoma). The study uses a mixed-methods approach (quantitative PROMs questionnaires and end-of-study surveys with qualitative interviews) and commenced in May 2021 in surgical and medical melanoma clinics at two sites in metropolitan Sydney, Australia. The primary outcomes are measures of feasibility and acceptability, comprising descriptive questionnaire completion statistics, and proportion of patients who reported that these PROMs were easy to complete and measured items they considered important. Clinician and clinic staff views will be canvassed on the appropriateness of these PROMs for their patients, change in referral practice and uptake and incorporation into routine practice. Secondary aims include measurement of improvements in patients' emotional and physical health and well-being, and utility of real-time data capture and clinician feedback. All participants will complete the Distress Thermometer and EQ-5D-5L questionnaires in the clinic using a tablet computer at baseline and two to three subsequent follow-up appointments. Participants who report a score of 4 or higher on the Distress Thermometer will be triaged to complete an additional three questionnaires: the QLQ-C30, Depression, Anxiety and Stress Scale and Melanoma Concerns Questionnaire-28. Results will be generated in real time; patients with psychosocial distress or poor quality of life will discuss possible referral to appropriate allied health services with their clinician. Thematic analysis of interviews will be conducted. ETHICS AND DISSEMINATION: Ethics approval obtained from St Vincent's Hospital Human Research Ethics Committee on 19 September 2019 (2019/ETH10558), with amendments approved on 8 June 2022. Patient consent is obtained electronically prior to questionnaire commencement. Dissemination strategies will include publication in peer-reviewed journals and presentation at international conferences, tailored presentations for clinical societies and government bodies, organisational reporting through multidisciplinary meetings and research symposia for local clinicians and clinic staff, and more informal, lay reports and presentations for consumer melanoma representative bodies and patient participants and their families. TRIAL REGISTRATION NUMBER: ACTRN12620001149954.

A randomised controlled trial to evaluate the impact of indoor living space on dairy cow production, reproduction and behaviour.

As a global society, we have a duty to provide suitable care and conditions for farmed livestock to protect animal welfare and ensure the sustainability of our food supply. The suitability and biological impacts of housing conditions for intensively farmed animals is a complex and emotive subject, yet poorly researched, meaning quantitative evidence to inform policy and legislation is lacking. Most dairy cows globally are housed for some duration during the year, largely when climatic conditions are unfavourable. However, the impact on biology, productivity and welfare of even the most basic housing requirement, the quantity of living space, remains unknown. We conducted a long-term (1-year), randomised controlled trial (CONSORT 10 guidelines) to investigate the impact of increased living space (6.5 m2 vs 3 m2 per animal) on critical aspects of cow biology, behaviour and productivity. Adult Holstein dairy cows (n = 150) were continuously and randomly allocated to a high or control living space group with all other aspects of housing remaining identical between groups. Compared to cows in the control living space group, cows with increased space produced more milk per 305d lactation (primiparous: 12,235 L vs 11,592 L, P < 0.01; multiparous: 14,746 L vs 14,644 L, P < 0.01) but took longer to become pregnant after calving (primiparous: 155 d vs 83 d, P = 0.025; multiparous: 133 d vs 109 d). In terms of behaviour, cows with more living space spent significantly more time in lying areas (65 min/d difference; high space group: 12.43 h/day, 95% CI = 11.70-13.29; control space group: 11.42 h/day, 95% CI = 10.73-12.12) and significantly less time in passageways (64 min/d), suggesting enhanced welfare when more space was provided. A key physiological difference between groups was that cows with more space spent longer ruminating each day. This is the first long term study in dairy cows to demonstrate that increased living space results in meaningful benefits in terms of productivity and behaviour and suggests that the interplay between farmed animals and their housed environment plays an important role in the concepts of welfare and sustainability of dairy farming.