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Background: Distant metastases in non-small-cell lung cancer (NSCLC) are a poor prognostic factor that negatively impact quality of life. The central nervous system (CNS) is a common site of distant progression in epidermal growth factor receptor-mutated (EGFRm) NSCLC. Osimertinib is a third-generation EGFR-tyrosine kinase inhibitor recommended for advanced EGFRm NSCLC and as adjuvant treatment for resected EGFRm NSCLC. In LAURA (NCT03521154), osimertinib demonstrated statistically significant improvement in progression-free survival (PFS) versus placebo in unresectable stage III EGFRm NSCLC without progression during/following chemoradiotherapy (CRT). CNS efficacy and time to death or distant metastases (TTDM) analyses are reported here., Patients and Methods: Patients without progression during/following definitive platinum-based CRT were randomised 2 : 1 to receive osimertinib (80 mg daily) or placebo until progression [by blinded independent central review (BICR)] or discontinuation. The primary endpoint was PFS by BICR. CNS PFS by neuroradiologist BICR and TTDM by BICR were secondary endpoints., Results: Overall, 216 patients were randomised (143 osimertinib, 73 placebo). Median CNS PFS by neuroradiologist BICR was not reached [95% confidence interval (CI) not calculable (NC)-NC] with osimertinib versus 14.9 months (95% CI 7.4 months-NC) with placebo; hazard ratio (HR) for CNS PFS: 0.17 (95% CI 0.09-0.32). CNS PFS analysis by investigator assessment was consistent with BICR assessment. The cumulative incidence of CNS progression at 12 months was 9% (95% CI 5% to 14%) with osimertinib and 36% (95% CI 24% to 47%) with placebo. There was clinically meaningful improvement in TTDM with osimertinib versus placebo; HR for TTDM: 0.21 (95% CI 0.11-0.38). The cumulative incidence of distant metastases at 12 months was 11% (95% CI 6% to 17%) with osimertinib and 37% (95% CI 26% to 48%) with placebo., Conclusions: Osimertinib demonstrated clinically meaningful improvements in CNS PFS and TTDM versus placebo, supporting osimertinib post-CRT as the standard of care in unresectable stage III EGFRm NSCLC., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Previous research has shown that informal caregiver burden can have deleterious effects on patient recovery; however, this relationship has yet to be investigated in patients undergoing coronary artery bypass graft (CABG) surgery. This study aimed to examine the impact of the change of caregiver burden from pre- to post-surgery on patients' mental and physical health after CABG surgery. Ninety patient-caregiver dyads were assessed one month before the surgery, two months and one year after the surgery. Caregivers completed the Oberst Burden Scale to measure caregiver burden. Patients completed the Beck Depression Inventory to measure depressive symptoms, a subscale of the Hospital Anxiety and Depression Scale to measure anxiety symptoms, the Short Form-12 health assessment to measure health-related quality of life, and the Coronary Revascularisation Outcomes Questionnaire to measure surgery symptoms. Hierarchical linear regression analyses were conducted to explore the association between change in caregiver burden and post-surgery patient outcomes. A greater increase in caregiver burden from pre- to two-months post-surgery significantly predicted higher patients' depressive symptoms (β = 0.179, p = 0.010), anxiety symptoms (β = 0.114, p = 0.017), reported post-surgery symptoms (β = 0.335, p = 0.008) and reduced physical health-related quality of life (β = -0.358, p = 0.003), after controlling for a wide range of covariates. These findings were not replicated at a one-year follow-up. These results provide insights into the impact of caregiver burden on patient distress following CABG surgery, supporting the idea of psychological support interventions for caregivers to increase patients' short-term recovery outcomes., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Digital health interventions (DHIs) could support prevention and management of cardiometabolic disease. However, those who may benefit most often experience barriers to awareness and adoption of these interventions., Objective: Among South Asian individuals, we evaluated user experience of DHIs for prevention and management of cardiometabolic disease, aiming to understand barriers and facilitators to initial and ongoing use., Methods: Among South Asian individuals recruited via primary care, community organizations, and snowball methods (n=18), we conducted "think-aloud" interviews using a reflective and reactive approach. Participants included nonusers, as well as those that used a range of DHIs as part of monitoring and improving their health. Participants were asked to think aloud while completing a task they routinely do in a familiar DHI, as well as while setting up and completing a search task in a novel DHI; they were encouraged to behave as if unobserved., Results: Lack of cultural specificity was highlighted as reducing relevance and usability, particularly relating to dietary change. Preferred features reflected individual health beliefs and behaviors, digital skills, and trust in DHIs. For example, tracking blood glucose was considered by some to be positive, while for others it caused distress and anxiety. Similarly, some users found the novel DHI to be extremely simple to set up and use, and others grew frustrated navigating through initial interfaces. Many participants raised concerns about data privacy and needing to agree to terms and conditions that they did not understand. Participants expressed that with information and support from trusted sources, they would be interested in using DHIs as part of self-management., Conclusions: DHIs may support South Asians to prevent and manage cardiometabolic disease, but it is important to consider the needs of specific user groups in DHI development, design, and implementation. Despite motivation to make health changes, digital barriers are common. Cultural appropriateness and trusted sources (such as health care providers and community organizations) have roles in increasing awareness and enabling individuals to access and use DHIs., (© Mel Ramasawmy, Dan Roland Persson, David Sunkersing, Paramjit Gill, Kamlesh Khunti, Lydia Poole, Wasim Hanif, Ann Blandford, Madiha Sajid, Fiona Stevenson, Nushrat Khan, Amitava Banerjee. Originally published in JMIR Human Factors (https://humanfactors.jmir.org).)

Objectives: Motivational Interviewing (MI), a client-centered approach that seeks to evoke and resolve ambivalence, and health education (HE), which provides health information and advice, may both provide some benefit to unmotivated smokers. In HE, it is possible that client language reflective of new learning, or "learning talk" (LT), and rejection of health advice, or "rejection talk," (RT), may uniquely reflect intent of subsequent behavior change., Methods: This project utilized MI and HE sessions from two randomized clinical trials (RCTs), one in a low-income, diverse community civilian sample of 255 unmotivated smokers, and the other in a sample of Veterans with mental illness who were unmotivated smokers (n = 55). Mixed methods approaches were utilized to reliably code sessions using the Motivational Interviewing Skill Code 2.5 (MISC 2.5) 1 and a refined Learning Talk coding system 2 ., Results: Reliability of LT and RT codes ranged from fair to excellent (ICCs from 0.43-0.93)., Conclusion: LT appears to be a unique construct and its impact on post-session changes in smoking is warranted., Practice Implications: This system can be used in a study to code existing interventions for smokers using both MI and HE techniques and relate in-session client LT to subsequent smoking behaviors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

Importance: Current treatments for idiopathic pulmonary fibrosis slow the rate of lung function decline, but may be associated with adverse events that affect medication adherence. In phase 2 trials, pamrevlumab (a fully human monoclonal antibody that binds to and inhibits connective tissue growth factor activity) attenuated the progression of idiopathic pulmonary fibrosis without substantial adverse events., Objective: To assess the efficacy and safety of pamrevlumab for patients with idiopathic pulmonary fibrosis., Design, Setting, and Participants: Phase 3 randomized clinical trial including 356 patients aged 40 to 85 years with idiopathic pulmonary fibrosis who were not receiving antifibrotic treatment with nintedanib or pirfenidone at enrollment. Patients were recruited from 117 sites in 9 countries between July 18, 2019, and July 29, 2022; the last follow-up encounter occurred on August 28, 2023., Interventions: Pamrevlumab (30 mg/kg administered intravenously every 3 weeks; n = 181) or placebo (n = 175) for 48 weeks., Main Outcomes and Measures: The primary outcome was absolute change in forced vital capacity (FVC) from baseline to week 48. There were 5 secondary outcomes (including time to disease progression, which was defined as a decline of ≥10% in predicted FVC or death). The exploratory outcomes included patient-reported symptoms. Adverse events were reported., Results: Among 356 patients (mean age, 70.5 years; 258 [72.5%] were men; 221 [62.1%] were White), 277 (77.8%) completed the trial. There was no significant between-group difference for absolute change in FVC from baseline to week 48 (least-squares mean, -260 mL [95% CI, -350 to -170 mL] in the pamrevlumab group vs -330 mL [95% CI, -430 to -230 mL] in the placebo group; mean between-group difference, 70 mL [95% CI, -60 to 190 mL], P = .29). There were no significant between-group differences in any of the secondary outcomes or in the patient-reported outcomes. In the pamrevlumab group, there were 160 patients (88.4%) with treatment-related adverse events and 51 patients (28.2%) with serious adverse events vs 151 (86.3%) and 60 (34.3%), respectively, in the placebo group. During the study, 23 patients died in each group (12.7% in the pamrevlumab group vs 13.1% in the placebo group)., Conclusions and Relevance: Among patients with idiopathic pulmonary fibrosis treated with pamrevlumab or placebo, there was no statistically significant between-group difference for the primary outcome of absolute change in FVC from baseline to week 48., Trial Registration: ClinicalTrials.gov Identifier: NCT03955146.

Neural tissue engineering has emerged as a promising field that aims to create functional neural tissue for therapeutic applications, drug screening, and disease modelling. It is becoming evident in the literature that this goal requires development of three-dimensional (3D) constructs that can mimic the complex microenvironment of native neural tissue, including its biochemical, mechanical, physical, and electrical properties. These 3D models can be broadly classified as self-assembled models, which include spheroids, organoids, and assembloids, and engineered models, such as those based on decellularized or polymeric scaffolds. Self-assembled models offer advantages such as the ability to recapitulate neural development and disease processes in vitro , and the capacity to study the behaviour and interactions of different cell types in a more realistic environment. However, self-assembled constructs have limitations such as lack of standardised protocols, inability to control the cellular microenvironment, difficulty in controlling structural characteristics, reproducibility, scalability, and lengthy developmental timeframes. Integrating biomimetic materials and advanced manufacturing approaches to present cells with relevant biochemical, mechanical, physical, and electrical cues in a controlled tissue architecture requires alternate engineering approaches. Engineered scaffolds, and specifically 3D hydrogel-based constructs, have desirable properties, lower cost, higher reproducibility, long-term stability, and they can be rapidly tailored to mimic the native microenvironment and structure. This review explores 3D models in neural tissue engineering, with a particular focus on analysing the benefits and limitations of self-assembled organoids compared with hydrogel-based engineered 3D models. Moreover, this paper will focus on hydrogel based engineered models and probe their biomaterial components, tuneable properties, and fabrication techniques that allow them to mimic native neural tissue structures and environment. Finally, the current challenges and future research prospects of 3D neural models for both self-assembled and engineered models in neural tissue engineering will be discussed.

Competing Interests: LP is supported by the National Institute of Health Research (grant number NIHR155654). RH is supported by the Academy of Medical Sciences, the Wellcome Trust, the Government Department of Business, Energy and Industrial Strategy, the British Heart Foundation, and Diabetes UK Springboard Award (grant number SBF006\1036).

Integration of bioelectronic devices in clinical practice is expanding rapidly, focusing on conditions ranging from sensory to neurological and mental health disorders. While platinum (Pt) electrodes in neuromodulation devices such as cochlear implants and deep brain stimulators have shown promising results, challenges still affect their long-term performance. Key among these are electrode and device longevity in vivo, and formation of encapsulating fibrous tissue. To overcome these challenges, organic conductors with unique chemical and physical properties are being explored. They hold great promise as coatings for neural interfaces, offering more rapid regulatory pathways and clinical implementation than standalone bioelectronics. This study provides a comprehensive review of the potential benefits of organic coatings in neuromodulation electrodes and the challenges that limit their effective integration into existing devices. It discusses issues related to metallic electrode use and introduces physical, electrical, and biological properties of organic coatings applied in neuromodulation. Furthermore, previously reported challenges related to organic coating stability, durability, manufacturing, and biocompatibility are thoroughly reviewed and proposed coating adhesion mechanisms are summarized. Understanding organic coating properties, modifications, and current challenges of organic coatings in clinical and industrial settings is expected to provide valuable insights for their future development and integration into organic bioelectronics., (© 2023 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Cardiovascular disease and diabetes are leading causes of morbidity and mortality worldwide. Social inequalities in the distribution of these diseases across the population exist. The aim of the current study was to examine the additive effect of socioeconomic position and a known biological risk marker (C-reactive protein [CRP]) for future incident cardiometabolic disease. We used data from the English Longitudinal Study of Ageing (N = 5410). Tertiles of net financial wealth and CRP (>3 mg/L) were measured at wave 2 (2004/05) and disease incidence (coronary heart disease [CHD], stroke, diabetes/high blood glucose) was reported across the subsequent 14 years of follow-up (2006-2019). Individual diseases were modelled as well as cardiometabolic multimorbidity which was defined as 2 or more incident cardiometabolic disease diagnoses over follow-up. Participants were free from the disease of interest at baseline. Cox proportional hazard and logistic regression analyses were used controlling for sociodemographic, lifestyle and health-related covariates. After adjusting for all covariates, the combination of low wealth and elevated CRP was an independent predictor of incident diabetes/high blood glucose (Hazard Ratio (HR) = 2.14; 95% Confidence Interval (C.I.) = 1.49-3.07), CHD (HR = 2.48, 95% C.I. = 1.63-3.76), stroke (HR = 1.55; 95% C.I. = 1.18-2.04), relative to high wealth/low CRP. Low wealth and elevated CRP was also an independent predictor of incident cardiometabolic multimorbidity (Odds Ratio = 2.22, 95% C.I. = 1.16-4.28) in age and sex adjusted models. The presence of both low wealth and elevated CRP was implicated in the onset of CHD, stroke, diabetes/high blood glucose, and cardiometabolic multimorbidity up to 14 years later, reflecting the role of psychobiological processes in predicting disease burden. Our results reinforce calls for efforts to tackle structural inequalities to improve healthy ageing trajectories., (© 2023 The Authors.)

New technologies and disruptions related to Coronavirus disease-2019 have led to expansion of decentralized approaches to clinical trials. Remote tools and methods hold promise for increasing trial efficiency and reducing burdens and barriers by facilitating participation outside of traditional clinical settings and taking studies directly to participants. The Trial Innovation Network, established in 2016 by the National Center for Advancing Clinical and Translational Science to address critical roadblocks in clinical research and accelerate the translational research process, has consulted on over 400 research study proposals to date. Its recommendations for decentralized approaches have included eConsent, participant-informed study design, remote intervention, study task reminders, social media recruitment, and return of results for participants. Some clinical trial elements have worked well when decentralized, while others, including remote recruitment and patient monitoring, need further refinement and assessment to determine their value. Partially decentralized, or "hybrid" trials, offer a first step to optimizing remote methods. Decentralized processes demonstrate potential to improve urban-rural diversity, but their impact on inclusion of racially and ethnically marginalized populations requires further study. To optimize inclusive participation in decentralized clinical trials, efforts must be made to build trust among marginalized communities, and to ensure access to remote technology., Competing Interests: Dr Benjamin, Jr. reports consultancy for Allergan, Melinta Therapeutics, and Sun Pharma Advanced Research Co. The remaining authors declare no conflicts of interest., (© The Author(s) 2023.)

Background: Among patients with resected, epidermal growth factor receptor ( EGFR )-mutated, stage IB to IIIA non-small-cell lung cancer (NSCLC), adjuvant osimertinib therapy, with or without previous adjuvant chemotherapy, resulted in significantly longer disease-free survival than placebo in the ADAURA trial. We report the results of the planned final analysis of overall survival., Methods: In this phase 3, double-blind trial, we randomly assigned eligible patients in a 1:1 ratio to receive osimertinib (80 mg once daily) or placebo until disease recurrence was observed, the trial regimen was completed (3 years), or a discontinuation criterion was met. The primary end point was investigator-assessed disease-free survival among patients with stage II to IIIA disease. Secondary end points included disease-free survival among patients with stage IB to IIIA disease, overall survival, and safety., Results: Of 682 patients who underwent randomization, 339 received osimertinib and 343 received placebo. Among patients with stage II to IIIA disease, the 5-year overall survival was 85% in the osimertinib group and 73% in the placebo group (overall hazard ratio for death, 0.49; 95.03% confidence interval [CI], 0.33 to 0.73; P<0.001). In the overall population (patients with stage IB to IIIA disease), the 5-year overall survival was 88% in the osimertinib group and 78% in the placebo group (overall hazard ratio for death, 0.49; 95.03% CI, 0.34 to 0.70; P<0.001). One new serious adverse event, pneumonia related to coronavirus disease 2019, was reported after the previously published data-cutoff date (the event was not considered by the investigator to be related to the trial regimen, and the patient fully recovered). Adjuvant osimertinib had a safety profile consistent with that in the primary analysis., Conclusions: Adjuvant osimertinib provided a significant overall survival benefit among patients with completely resected, EGFR -mutated, stage IB to IIIA NSCLC. (Funded by AstraZeneca; ADAURA ClinicalTrials.gov number, NCT02511106.)., (Copyright © 2023 Massachusetts Medical Society.)

Importance: Depression is associated with an increased risk of physical illness, but the most common causes of hospitalization among people with depression are unclear., Objective: To examine the association of depression with an array of physical conditions requiring hospital treatment., Design, Setting, and Participants: In this outcomewide prospective multicohort study, primary analysis was based on data from the UK Biobank, a population-based study in the United Kingdom. Analyses were repeated in an independent data set of 2 cohorts in Finland, a population-based study and an occupational cohort. Data analysis was conducted between April and September 2022., Exposures: Self-reported depression, recurrent severe major depression, recurrent moderate major depression, and a single major depressive episode., Main Outcomes and Measures: A total of 77 common health conditions ascertained from linkage data to national hospital and mortality registries., Results: The analytical sample of UK Biobank participants consisted of 130 652 individuals (71 565 women [54.8%]; 59 087 men [45.2%]; mean [SD] age at baseline, 63.3 [7.8] years). The pooled data from the Finnish replication cohorts included 109 781 participants (82 921 women [78.6%]; 26 860 men [21.4%]; mean [SD] age, 42 [10.8] years). In the main analysis, severe/moderately severe depression was associated with the incidence of 29 nonoverlapping conditions requiring hospital treatment during a 5-year follow-up. Twenty-five of these associations remained after adjustment for confounders and multiple testing (adjusted hazard ratio [HR] range, 1.52-23.03) and were confirmed in the analysis of the Finnish cohorts. These included sleep disorders (HR, 5.97; 95% CI, 3.27-10.89), diabetes (HR, 5.15; 95% CI, 2.52-10.50), ischemic heart disease (HR, 1.76; 95% CI, 1.36-2.29), chronic obstructive bronchitis (HR, 4.11; 95% CI, 2.56-6.60), bacterial infections (HR, 2.52; 95% CI, 1.99-3.19), back pain (HR, 3.99; 95% CI, 2.96-5.38), and osteoarthritis (HR, 1.80; 95% CI, 1.46-2.20). The highest cumulative incidence was observed for endocrine and related internal organ diseases (245 per 1000 persons with depression; risk difference relative to unaffected individuals: 9.8%), musculoskeletal diseases (91 per 1000 persons; risk difference, 3.7%), and diseases of the circulatory system and blood (86 per 1000 persons; risk difference, 3.9%). The cumulative incidence was lower for hospital-treated mental, behavioral, and neurological disorders (20 in 1000 persons; risk difference, 1.7%). Depression was also associated with disease progression in people with prevalent heart disease or diabetes, and for 12 conditions, there was evidence of a bidirectional relationship., Conclusions and Relevance: In this study, the most common causes of hospitalization in people with depression were endocrine, musculoskeletal, and vascular diseases, not psychiatric disorders. These findings suggest that depression should be considered as a target for the prevention of physical and mental disease.

Fibrous tissue encapsulation can impact the performance of bioelectrodes following implantation. For example, significant increases in electrode impedance can occur within four weeks post-implantation. A key limitation hindering the understanding of host response-mediated impedance change is the reliance on animal models or complex in vitro cell cultures for electrode testing. This study aimed to develop an in vitro acellular model that can reproduce the changes in electrical properties of bioelectrodes that occur due to host responses following implantation. Specifically, the effect of synthetic, biological, and bio-synthetic co-polymer hydrogel coatings on electrode impedance was measured. Poly(vinyl alcohol) (PVA), gelatin, and PVA-gelatin co-polymers (10 and 20 wt%) were coated onto platinum (Pt) electrodes. Polarisation and access voltage, key components of the voltage response that relate to cell adhesion and protein adsorption respectively, were measured pre and post hydrogel coating and the impedance change was calculated. Results showed that increasing the polymer concentration affects the access resistance regardless of the hydrogel chemistry but only high content gelatin hydrogels increased the polarisation resistance. The increase in total impedance was ~ 2-fold of bare Pt, similar to clinical observations. This study demonstrated that an acellular fibrosis model using hydrogels could reproduce the impedance changes observed in vivo. Such a model system will support research to better understand in vivo changes in electrical properties and the longer term function of neuroprosthetic electrodes.Clinical Relevance-This study proposes an acellular fibrosis model for preclinical research. This will support the design of improved clinical stimulation strategies and better understanding of the mechanisms of impedance change at the device-tissue interface.

Objective: Dysregulated stress responsivity has been linked with weight gain in healthy samples. However, the relationship between disturbances in stress-related biology and changes in weight in people with type 2 diabetes (T2D) is unclear., Method: A total of 66 participants with T2D underwent laboratory stress-testing in 2011-2012. Cardiovascular, neuroendocrine and inflammatory responses to standardised mental stress were assessed, and Body Mass Index (BMI) was measured. Participants self-reported information on BMI in 2019. Associations between stress-related biological responses and BMI at follow-up were modelled using linear regression adjusting for age, sex, resting biological levels and baseline BMI., Results: Blunted diastolic blood pressure reactivity (B = -0.092, 95% CI -0.177; -0.007, p = 0.034) as well as poorer systolic blood pressure (B = -0.050, 95% CI -0.084; - 0.017, p = 0.004), diastolic blood pressure (B = -0.068, 95% CI -0.132; -0.004, p = 0.034) and heart rate (B = -0.122, 95% CI -0.015;-0.230, p = 0.027) recovery post-stress were associated with higher BMI 7.5 years later. Greater interleukin-1 receptor antagonist (B = 16.93, 95% CI 6.20; 27.67, p = 0.003) and monocyte chemoattractant protein-1 reactivity (B = 0.04, 95% CI 0.002; 0.084, p = 0.041) were associated with weight gain. No significant associations were detected for interleukin-6 or laboratory cortisol measures., Conclusion: Disturbances in stress-related biology may promote weight gain in people with T2D. Research with a larger sample size is required to explore associations between stress responsivity and BMI in people with T2D., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent health policies in the United Kingdom (UK) and internationally have focussed on digitisation of healthcare. We examined UK policies for evidence of government action addressing health inequalities and digital health, using cardiometabolic disease as an exemplar. Using a systematic search methodology, we identified 87 relevant policy documents published between 2010 and 2022. We found increasing emphasis on digital health, including for prevention, diagnosis and management of cardiometabolic disease. Several policies also focused on tackling health inequalities and improving digital access. The COVID-19 pandemic amplified inequalities. No policies addressed ethnic inequalities in digital health for cardiometabolic disease, despite high prevalence in minority ethnic communities. Our findings suggest that creating opportunities for digital inclusion and reduce longer-term health inequalities, will require future policies to focus on: the heterogeneity of ethnic groups; cross-sectoral disadvantages which contribute to disease burden and digital accessibility; and disease-specific interventions which lend themselves to culturally tailored solutions., (© 2023. The Author(s).)

One challenge for multisite clinical trials is ensuring that the conditions of an informative trial are incorporated into all aspects of trial planning and execution. The multicenter model can provide the potential for a more informative environment, but it can also place a trial at risk of becoming uninformative due to lack of rigor, quality control, or effective recruitment, resulting in premature discontinuation and/or non-publication. Key factors that support informativeness are having the right team and resources during study planning and implementation and adequate funding to support performance activities. This communication draws on the experience of the National Center for Advancing Translational Science (NCATS) Trial Innovation Network (TIN) to develop approaches for enhancing the informativeness of clinical trials. We distilled this information into three principles: (1) assemble a diverse team, (2) leverage existing processes and systems, and (3) carefully consider budgets and contracts. The TIN, comprised of NCATS, three Trial Innovation Centers, a Recruitment Innovation Center, and 60+ CTSA Program hubs, provides resources to investigators who are proposing multicenter collaborations. In addition to sharing principles that support the informativeness of clinical trials, we highlight TIN-developed resources relevant for multicenter trial initiation and conduct., Competing Interests: Co-Author, Daniel K. Benjamin, Jr., Duke Clinical Research Institute, reports consultancies with AbbieVie, PPD, and Syneos Health. No other authors have declared conflicts of interest or financial involvements that might potentially bias their work., (© The Author(s) 2023.)

For a single species, human kinship organization is both remarkably diverse and strikingly organized. Kinship terminology is the structured vocabulary used to classify, refer to, and address relatives and family. Diversity in kinship terminology has been analyzed by anthropologists for over 150 years, although recurrent patterning across cultures remains incompletely explained. Despite the wealth of kinship data in the anthropological record, comparative studies of kinship terminology are hindered by data accessibility. Here we present Kinbank, a new database of 210,903 kinterms from a global sample of 1,229 spoken languages. Using open-access and transparent data provenance, Kinbank offers an extensible resource for kinship terminology, enabling researchers to explore the rich diversity of human family organization and to test longstanding hypotheses about the origins and drivers of recurrent patterns. We illustrate our contribution with two examples. We demonstrate strong gender bias in the phonological structure of parent terms across 1,022 languages, and we show that there is no evidence for a coevolutionary relationship between cross-cousin marriage and bifurcate-merging terminology in Bantu languages. Analysing kinship data is notoriously challenging; Kinbank aims to eliminate data accessibility issues from that challenge and provide a platform to build an interdisciplinary understanding of kinship., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Passmore et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Purpose: The open-label, phase III POSEIDON study evaluated tremelimumab plus durvalumab and chemotherapy (T + D + CT) and durvalumab plus chemotherapy (D + CT) versus chemotherapy alone (CT) in first-line metastatic non-small-cell lung cancer (mNSCLC)., Methods: Patients (n = 1,013) with EGFR / ALK wild-type mNSCLC were randomly assigned (1:1:1) to tremelimumab 75 mg plus durvalumab 1,500 mg and platinum-based chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression and one additional tremelimumab dose; durvalumab plus chemotherapy for up to four 21-day cycles, followed by durvalumab once every 4 weeks until progression; or chemotherapy for up to six 21-day cycles (with or without maintenance pemetrexed; all arms). Primary end points were progression-free survival (PFS) and overall survival (OS) for D + CT versus CT. Key alpha-controlled secondary end points were PFS and OS for T + D + CT versus CT., Results: PFS was significantly improved with D + CT versus CT (hazard ratio [HR], 0.74; 95% CI, 0.62 to 0.89; P = .0009; median, 5.5 v 4.8 months); a trend for improved OS did not reach statistical significance (HR, 0.86; 95% CI, 0.72 to 1.02; P = .0758; median, 13.3 v 11.7 months; 24-month OS, 29.6% v 22.1%). PFS (HR, 0.72; 95% CI, 0.60 to 0.86; P = .0003; median, 6.2 v 4.8 months) and OS (HR, 0.77; 95% CI, 0.65 to 0.92; P = .0030; median, 14.0 v 11.7 months; 24-month OS, 32.9% v 22.1%) were significantly improved with T + D + CT versus CT. Treatment-related adverse events were maximum grade 3/4 in 51.8%, 44.6%, and 44.4% of patients receiving T + D + CT, D + CT, and CT, respectively; 15.5%, 14.1%, and 9.9%, respectively, discontinued treatment because of treatment-related adverse events., Conclusion: D + CT significantly improved PFS versus CT. A limited course of tremelimumab added to durvalumab and chemotherapy significantly improved OS and PFS versus CT, without meaningful additional tolerability burden, representing a potential new option in first-line mNSCLC.

Background: Digital health interventions (DHIs) for the prevention and management of cardiometabolic diseases have become increasingly common. However, there is limited evidence for the suitability of these approaches in minority ethnic populations, who are at an increased risk of these diseases., Objective: This study aimed to investigate the use of DHIs for cardiovascular disease and type 2 diabetes among minority ethnic populations in countries with a majority of White, English-speaking populations, focusing on people who identified as South Asian, Black, or African American., Methods: A realist methodology framework was followed. A literature search was conducted to develop context-mechanism-outcome configurations, including the contexts in which DHIs work for the target minority ethnic groups, mechanisms that these contexts trigger, and resulting health outcomes. After systematic searches, a qualitative analysis of the included studies was conducted using deductive and inductive coding., Results: A total of 15 studies on the uptake of DHIs for cardiovascular disease or diabetes were identified, of which 13 (87%) focused on people with an African-American background. The review found evidence supporting the use of DHIs in minority ethnic populations when specific factors are considered in implementation and design, including patients' beliefs, health needs, education and literacy levels, material circumstances, culture, social networks, and wider community and the supporting health care systems., Conclusions: Our context-mechanism-outcome configurations provide a useful guide for the future development of DHIs targeted at South Asian and Black minority ethnic populations, with specific recommendations for improving cultural competency and promoting accessibility and inclusivity of design., (©Aumeya Goswami, Lydia Poole, Zareen Thorlu-Bangura, Nushrat Khan, Wasim Hanif, Kamlesh Khunti, Paramjit Gill, Madiha Sajid, Ann Blandford, Fiona Stevenson, Amitava Banerjee, Mel Ramasawmy. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 06.01.2023.)

Dementia is a growing concern in Canada, affecting peoples' health and raising the cost of care. Between June and October 2019, we conducted an environmental scan to identify primary care models, strategies, and resources for dementia care from 11 pre-selected countries and assess their impact on quality-of-life measures. Search strategies included a rapid scoping review, grey literature search, and discussions with stakeholders. Eighteen primary care-based models of dementia care were identified. Common factors include team-based care, centralized care/case coordination, individual treatment plans, a stepped-care approach, and support for care partners. Five provinces had released a dementia strategy. Evidence of positive outcomes supported primary care-based models for dementia care, although only one model demonstrated evidence of impact on quality of life. Although these findings are encouraging, further research is needed to identify primary care-based models of dementia care that demonstrably improve quality of life for people living with dementia and their care partners.

BRCA1 is a well-known breast cancer risk gene, involved in DNA damage repair via homologous recombination (HR) and replication fork protection. Therapy resistance was linked to loss and amplification of the BRCA1 gene causing inferior survival of breast cancer patients. Most studies have focused on the analysis of complete loss or mutations in functional domains of BRCA1 . How mutations in non-functional domains contribute to resistance mechanisms remains elusive and was the focus of this study. Therefore, clones of the breast cancer cell line MCF7 with indels in BRCA1 exon 9 and 14 were generated using CRISPR/Cas9. Clones with successful introduced BRCA1 mutations were evaluated regarding their capacity to perform HR, how they handle DNA replication stress (RS), and the consequences on the sensitivity to MMC, PARP1 inhibition, and ionizing radiation. Unexpectedly, BRCA1 mutations resulted in both increased sensitivity and resistance to exogenous DNA damage, despite a reduction of HR capacity in all clones. Resistance was associated with improved DNA double-strand break repair and reduction in replication stress (RS). Lower RS was accompanied by increased activation and interaction of proteins essential for the S phase-specific DNA damage response consisting of HR proteins, FANCD2, and CHK1.

Background: Despite considerable advancements in Upper Gastrointestinal Cancer (UGIC) care in Australia and Aotearoa New Zealand (AAoNZ), the absolute number of deaths remains high. Clinical Quality and Safety Registries (CQRs) enable benchmarking and performance appraisal, however an AAoNZ CQR does not exist. To create this, we first aim to identify all national and international UGIC CQRs and amalgamate their data fields and definitions through a systematic review., Methods: A Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) compliant systematic review was performed using Scopus, Embase, Cochrane and MEDLINE databases. Human studies, in English, reporting on the development of and/or results of all CQRs focused on UGIC were included. Individual data fields were extracted and placed into four categories. Data fields could be further synthesized into data field subcategories if there were direct similarities among studies., Results: A total of 32 studies-23 national audits or registries and nine international benchmarking studies-were included, encompassing 899 073 patients in 48 countries. Of the total of 1710 individual data fields, 1526 (89.2%) were reported with a definition. The most number of data fields related to Treatment Factors (41.2%), with least number pertaining to Outcomes (7.8%)., Conclusions: This systematic review has amalgamated all data fields and definitions from UGIC CQRs or studies. Establishing an AAoNZ Clinical and Quality Safety Registry for our population will enable us to benchmark the performance of our UGIC care internationally. Further studies are indicated in the context of the use of the Delphi method to facilitate this process., (© 2022 Royal Australasian College of Surgeons.)

Background: People with intellectual disabilities are at risk of experiencing stigma and require the skills and confidence to deal with stigma in their daily lives., Method: Development and piloting of a 5-session manualised psychosocial group intervention designed to increase the capacity of people with intellectual disabilities aged 16+ to manage and resist stigma. Ten pre-existing groups (N = 67) in third sector and education settings participated. Interviews with participants (n = 26), facilitators (n = 9) and significant others (n = 7) 2-4 months after the intervention assessed perceived impact., Results: Perceived benefits of the intervention for participants included increased understanding, improved connections with others, drive for advocacy, increased activity and self-efficacy, and opportunity to process difficult events and emotions. Differential impact depending on individuals' pre-existing self-advocacy skills was noted., Conclusions: This early-stage study indicates that further evaluation is merited to examine feasibility and outcomes of the STORM intervention., (© 2022 The Authors. Journal of Applied Research in Intellectual Disabilities published by John Wiley & Sons Ltd.)

Background: Digital health interventions have become increasingly common across health care, both before and during the COVID-19 pandemic. Health inequalities, particularly with respect to ethnicity, may not be considered in frameworks that address the implementation of digital health interventions. We considered frameworks to include any models, theories, or taxonomies that describe or predict implementation, uptake, and use of digital health interventions., Objective: We aimed to assess how health inequalities are addressed in frameworks relevant to the implementation, uptake, and use of digital health interventions; health and ethnic inequalities; and interventions for cardiometabolic disease., Methods: SCOPUS, PubMed, EMBASE, Google Scholar, and gray literature were searched to identify papers on frameworks relevant to the implementation, uptake, and use of digital health interventions; ethnically or culturally diverse populations and health inequalities; and interventions for cardiometabolic disease. We assessed the extent to which frameworks address health inequalities, specifically ethnic inequalities; explored how they were addressed; and developed recommendations for good practice., Results: Of 58 relevant papers, 22 (38%) included frameworks that referred to health inequalities. Inequalities were conceptualized as society-level, system-level, intervention-level, and individual. Only 5 frameworks considered all levels. Three frameworks considered how digital health interventions might interact with or exacerbate existing health inequalities, and 3 considered the process of health technology implementation, uptake, and use and suggested opportunities to improve equity in digital health. When ethnicity was considered, it was often within the broader concepts of social determinants of health. Only 3 frameworks explicitly addressed ethnicity: one focused on culturally tailoring digital health interventions, and 2 were applied to management of cardiometabolic disease., Conclusions: Existing frameworks evaluate implementation, uptake, and use of digital health interventions, but to consider factors related to ethnicity, it is necessary to look across frameworks. We have developed a visual guide of the key constructs across the 4 potential levels of action for digital health inequalities, which can be used to support future research and inform digital health policies., (©Mel Ramasawmy, Lydia Poole, Zareen Thorlu-Bangura, Aneesha Chauhan, Mayur Murali, Parbir Jagpal, Mehar Bijral, Jai Prashar, Abigail G-Medhin, Elizabeth Murray, Fiona Stevenson, Ann Blandford, Henry W W Potts, Kamlesh Khunti, Wasim Hanif, Paramjit Gill, Madiha Sajid, Kiran Patel, Harpreet Sood, Neeraj Bhala, Shivali Modha, Manoj Mistry, Vinod Patel, Sarah N Ali, Aftab Ala, Amitava Banerjee. Originally published in JMIR Cardio (https://cardio.jmir.org), 11.08.2022.)

Background: Inflammatory dysregulation may be linked with mental health disturbances in people with Type 2 Diabetes (T2D), however no previous studies have examined longitudinal associations between inflammatory stress responses and mental health outcomes in T2D., Purpose: To better understand the biological mechanisms that might predispose people with T2D to poor mental health in the future., Methods: At baseline, 140 participants with T2D participated in a laboratory stress testing study (mean age = 64 years). Participants underwent two mental stress tasks and blood was sampled before and up to 45 min post-stress to detect plasma interleukin (IL)-6. The Center for Epidemiological Studies-Depression scale and the Short Form-36 Health Survey were completed at baseline and 7.5 years later. We tested associations between IL-6 stress responses and a) depression symptoms and b) mental health-related quality of life (QoL) at baseline and at follow-up using linear regression analyses adjusting for age, sex, and body mass index (BMI). Results: Up to 66 participants provided follow-up data. In cross-sectional analyses, increased IL-6 stress responses immediately post-task were associated with lower mental health-related quality of life ( B  = -21.73, p  = 0.005, 95% CI [-36.82, -6.63]) adjusting for age, sex, and BMI. In longitudinal analyses, increased IL-6 stress responses at 45 min post-task were associated with increased depressive symptoms ( B  = 10.31 p  = 0.048, 95% CI [0.10, 20.51]) and decreased mental health-related QoL ( B  = -21.18 p  = 0.031, 95% CI [-40.34, -2.02]) adjusting for age, sex, and BMI. The association between the 45-min IL-6 response and depressive symptoms at follow-up was diminished after further adjustment for physical health-related QoL and baseline depressive symptoms ( B  = 10.14, p  = 0.055, 95% CI [-0.21,20.48])., Conclusions: This study supports the link between inflammatory stress responsivity and future mental health outcomes in people with T2D. Further research involving a larger sample size is required., Competing Interests: None., (© 2022 The Author(s).)

People living with dementia (PLWD) have voiced a desire to remain in their home environment as long as possible; unfortunately, there is limited integrated person-and family-centered community support. To examine the need for tailored supports for PLWD and their family caregivers (caregiving dyad), a meeting was conducted in Spring 2020. Thirty key provincial stakeholders with diversity in geographic location, employer and/or organization, range of roles, and family representatives participated in the meeting. Stakeholders identified a series of gaps, including: (a) systemic gaps; (b) gaps between communities of practice; (c) underserved populations; (d) program content and delivery gaps; and (e) PLWD and family caregiver support gaps. With input from stakeholders, we highlighted the need for consistent resources for the caregiving dyad that are flexible, timely, and accessible, which are embedded in the community and led by qualified and trained staff. [ Journal of Gerontological Nursing, 48 (4), 26-32.].

Background: During the pandemic, there has been significant social media attention focused on the increased COVID-19 risks and impacts for people with dementia and their care partners. However, these messages can perpetuate misconceptions, false information, and stigma., Objective: This study used Twitter data to understand stigma against people with dementia propagated during the COVID-19 pandemic., Methods: We collected 1743 stigma-related tweets using the GetOldTweets application in Python from February 15 to September 7, 2020. Thematic analysis was used to analyze the tweets., Results: Based on our analysis, 4 main themes were identified: (1) ageism and devaluing the lives of people with dementia, (2) misinformation and false beliefs about dementia and COVID-19, (3) dementia used as an insult for political ridicule, and (4) challenging stigma against dementia. Social media has been used to spread stigma, but it can also be used to challenge negative beliefs, stereotypes, and false information., Conclusions: Dementia education and awareness campaigns are urgently needed on social media to address COVID-19-related stigma. When stigmatizing discourse on dementia is widely shared and consumed amongst the public, it has public health implications. How we talk about dementia shapes how policymakers, clinicians, and the public value the lives of people with dementia. Stigma perpetuates misinformation, pejorative language, and patronizing attitudes that can lead to discriminatory actions, such as the limited provision of lifesaving supports and health services for people with dementia during the pandemic. COVID-19 policies and public health messages should focus on precautions and preventive measures rather than labeling specific population groups., (©Juanita-Dawne Bacsu, Sarah Fraser, Alison L Chasteen, Allison Cammer, Karl S Grewal, Lauren E Bechard, Jennifer Bethell, Shoshana Green, Katherine S McGilton, Debra Morgan, Hannah M O’Rourke, Lisa Poole, Raymond J Spiteri, Megan E O'Connell. Originally published in JMIR Aging (https://aging.jmir.org), 31.03.2022.)

Background: While family caregivers provide 70-90% of care for people living in the community and assist with 10-30% of the care in congregate living, most healthcare providers do not meaningfully involve family caregivers as partners in care. Recent research recommends that the healthcare workforce receive competency-based education to identify, assess, support, and partner with family caregivers across the care trajectory., Objective: This paper reports a mixed-methods evaluation of a person-centered competency-based education program on Caregiver-Centered Care for the healthcare workforce., Methods: This foundational education was designed for all healthcare providers and trainees who work with family caregivers and is offered free online (caregivercare.ca). Healthcare providers from five healthcare settings (primary, acute, home, supportive living, long-term care) and trainees in medicine, nursing, and allied health were recruited via email and social media. We used the Kirkpatrick-Barr health workforce training evaluation framework to evaluate the education program, measuring various healthcare providers' learner satisfaction with the content (Level 1), pre-post changes in knowledge and confidence when working with family caregivers (Level 2), and changes in behaviors in practice (Level 3)., Results: Participants were primarily healthcare employees (68.9%) and trainees (21.7%) and represented 5 healthcare settings. Evaluation of the first 161 learners completing the program indicated that on a 5-point Likert scale, the majority were satisfied with the overall quality of the education (Mean(M) = 4.69; SD = .60). Paired T-tests indicated that out of a score of 50, post-education changes in knowledge and confidence to work with family caregivers was significantly higher than pre-education scores (pre M = 38.90, SD = 6.90; post M = 46.60, SD = 4.10; t(150) = - 16.75, p < .0001). Qualitative results derived from open responses echoed the quantitative findings in satisfaction with the education delivery as well as improvements in learners' knowledge and confidence., Conclusion: Health workforce education to provide person-centered care to all family caregivers is an innovative approach to addressing the current inconsistent system of supports for family caregivers. The education program evaluated here was effective at increasing self-reported knowledge and confidence to work with family caregivers., (© 2022. The Author(s).)

Cancer stem cells (CSCs) are a major cause of tumor therapy failure. This is mainly attributed to increased DNA repair capacity and immune escape. Recent studies have shown that functional DNA repair via homologous recombination (HR) prevents radiation-induced accumulation of DNA in the cytoplasm, thereby inhibiting the intracellular immune response. However, it is unclear whether CSCs can suppress radiation-induced cytoplasmic dsDNA formation. Here, we show that the increased radioresistance of ALDH1-positive breast cancer stem cells (BCSCs) in S phase is mediated by both enhanced DNA double-strand break repair and improved replication fork protection due to HR. Both HR-mediated processes lead to suppression of radiation-induced replication stress and consequently reduction of cytoplasmic dsDNA. The amount of cytoplasmic dsDNA correlated significantly with BCSC content (p=0.0002). This clearly indicates that HR-dependent avoidance of radiation-induced replication stress mediates radioresistance and contributes to its immune evasion. Consistent with this, enhancement of replication stress by inhibition of ataxia telangiectasia and RAD3 related (ATR) resulted in significant radiosensitization (SER37 increase 1.7-2.8 Gy, p<0.0001). Therefore, disruption of HR-mediated processes, particularly in replication, opens a CSC-specific radiosensitization option by enhancing their intracellular immune response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Meyer, Engel, Krause, Wagner, Poole, Dubrovska, Peitzsch, Rothkamm, Petersen and Borgmann.)

Objective: To understand how the lived experience of depression differs among patients with a long-term condition (LTC) compared with those without an LTC, and how the experience differs across different types of LTC., Design: Face-to-face, semistructured interviews., Setting: Primary care; General Practitioner (GP) surgeries in and around North London., Participants: 41 primary care patients with depression were recruited. Our sample comprised participants aged 55-75 years with depression only (n=12), depression and coronary heart disease (n=5), depression and type 2 diabetes (n=10) and depression and arthritis (n=14)., Results: Interviews were conducted, audio recorded, transcribed and analysed using thematic analysis. The results revealed that the cardinal diagnostic symptoms of depression (anhedonia, sadness) were experienced by all our participants regardless of LTC. However, the LTC did interact with depression by compounding somatic, cognitive and emotional symptoms, increasing disability and reducing independence, and hindering attempts at coping with mental illness. Our findings demonstrate common experiences across patients as well as key differences based on LTC., Conclusions: We suggest four key implications for future care practices of these patients: (1) not all participants with depression and LTC view their mental and physical health as interconnected; there should be allowances in care plans for separate treatment pathways; (2) key features of depression that affect LTC management are social withdrawal and lack of motivation to self-manage or access healthcare; (3) key features of LTCs that worsen depression are pain, the unpredictability of future health and progressive disability; (4) positive self-management of LTC could improve self-efficacy and therefore mood, and should be encouraged., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Understanding cultural differences between geographical regions is essential in delivering culturally appropriate healthcare. We aimed to describe the characteristics and outcomes of diverse clients using the Far North Mental Health and Wellbeing Service (FNS) and the Central West Health and Wellbeing Service (CWS)., Methods: We conducted a cohort study within Queensland, Australia, on all clients who received a mental health therapy session at either the FNS or the CWS. Patient data was prospective data collected form July 2019 to December 2020., Findings: There were1202 clients, with a median number of individual contacts per-client of 3.0 (IQR 2.0-6.0). There was 428 (35.6% 95% CI 32.90-38.39) males and 772 (64.2% 95% CI 61.44-66.94) females with a median age across the genders of 38.0 (IQR 28.0-51.0). There was 505 (42.0% 95% CI 39.20-44.86) identifying as Indigenous and 697 (58.0% 95% CI 55.14-60.80) as non-Indigenous Australians. The FNS had a significantly higher proportion of Indigenous clients (n=484; 54.8% 95% CI 51.46-58.13) as compared to the CWS (n=21; 6.6% 95% CI 4.12-9.89). Of the 1202 clients, 946 (78.7% 95% CI 76.28-80.99) had a socio-economic classification of 'most disadvantaged', consisting of 740 (83.8%) clients from the FNS and 206 (64.6%) clients from the CWS. The majority of presentations were for neurotic, stress-related and somatoform disorders (n=568; 47.3%), followed by mood affective disorders (n=310; 25.8%). The overall number of treatments strategies employed was 10798, equalling a median of 6.0 (IQR 4.0-9.0) strategies per-client, with the leading strategies being counselling/psychosocial (n=1394; 12.9%), reflective listening (n=1191; 11.0%), and strengths based reasoning (n=1116; 10.3%). There were 511 (42.5%) clients who completed the Kessler Psychological Distress Scale (K10/K5), with 493 (41.0%) clients not offered as deemed not culturally appropriate by the treating team. The mean initial K10/K5 score was 23.7 (SD 9.4) which significantly decreased (p<0.001) to 18.0 (SD 10.0) at final consultation., Interpretation: This study highlighted client socioeconomic differences between two geographically remote mental health services. It is essential that services are regionally co-designed to ensure cultural appropriateness., Funding: No funding to declare., Competing Interests: Ms. Middleton received paid employment by the PHN in the RFDS operating area, during the conduct of the study. The rest authors have no conflicts to declare. All experimental protocols were approved by the ACT Health Human Research Ethics Committee, on 7 April 2021 (number: 2021.LRE.00041). This publication was given final approval for publication by the Royal Flying Doctor Service Clinical Health Research Committee. All methods were carried out in accordance with relevant guidelines and regulations in the ethical approval and consent to participate. Client informed consent was obtained from all subjects or, if subjects are under 18, from a parent and/or legal guardian., (© 2022 The Author(s).)

In Australia, over half a million people are admitted to hospital every year as a result of injury, and where you live matters. Rural populations have disproportionately higher injury hospitalisation rates (1.5-2.5-fold), higher rates of preventable secondary complications, higher mortality rates (up to fivefold), and higher costs (threefold) than patients injured in major cities. These disparities scale up rapidly with increased remoteness, and shift the service needle from 'scoop and run' to 'continuum of care'. Poorer outcomes, however, are not solely due to longer retrieval distances or delays; they arise from inefficiencies in one or more potentially modifiable factors in the chain of survival. After discussing the burden of injury in Australia, we present a brief history of retrieval services in Queensland and discuss how remoteness requires a different kind of service delivery with many moving parts from point of injury to definitive care. We next address the ongoing challenges for the Australian Trauma Registry, and how centralisation of data from the metropolitan cities masks the inequities in rural and remote trauma. There is an urgent need for accurate data from all service providers around Australia to inform state and federal governments, and we highlight the paucity of trauma data analysis in North Queensland. Last, we identify some major gaps in treating rural and remote polytrauma and en-route patient stabilisation, and discuss the relevance of combat casualty care research and practices. We conclude that a greater emphasis should be placed on collecting more robust trauma patient records, as only accurate data will drive change.

Background: Recent research recommends the healthcare workforce receive competency-based education to identify, assess, support and partner with family-caregivers [FCGs} across the care trajectory. [1 2] Although the risk of FCG anxiety, burden, and loneliness to FCG's wellbeing is widely documented, typically education has been targeted towards FCG's to increase their care skills rather to educate healthcare providers to support FCG's caregiving and wellbeing. [3] OBJECTIVES: We will present the co-design process used to create a competency-based education program for the healthcare workforce that ensures a person-centered focus on FCGs and introduce our Health Workforce Caregiver-Centered Care Education focused on dementia. Co-design is the act of creating with stakeholders to ensure the results meet their needs and are usable., Project Description: We began by coining the concept "caregiver-centered care," defining it as: a collaborative working relationship between families and healthcare providers aimed at supporting FCGs in their caregiving role, decisions about services, care management, and advocacy [4 5] . From this definition, and working with multi-level interdisciplinary stakeholders we designed [6] and validated [7] a Caregiver-Centered Care Competency Framework in a Modified Delphi Process. Stakeholders (n= 101) including FCGs, health providers, policy makers, community organizations, research team, script writer, and educational designers then used effective practices for dementia education for the health workforce [8-11] to co-design the first or 'foundational' level of a Caregiver Centered Care education program., Results: Teaching and learning resources include six competency-aligned educational modules with videos and interactive exercises that encourage reflection. With the COVID-19 pandemic, we moved the education online (caregivercare.ca). In the first two months online, November 9, 2020-January 9, 2021, 352 healthcare providers completed the education. To date, learners' qualitative evaluations have been positive, "Very good information for professionals working with caregivers; especially relevant to homecare, geriatricians, allied health, and others working within the Seniors' Health realm. Engaging format that really evokes empathy for caregivers.", Discussion: We continue to use mixed methods to evaluate the Caregiver-Centered Care Education, for acceptability and effectiveness, in five care contexts (primary, acute, home, supportive living, long-term care)., Conclusion: We expect that our education will support caregiver-centered care in all settings providing dementia-related care., (© 2021 the Alzheimer's Association.)

Active implantable neurological devices like deep brain stimulators have been used over the past few decades to treat movement disorders such as those in people with Parkinson's disease and more recently, in psychiatric conditions like obsessive compulsive disorder. Electrode-tissue interfaces that support safe and effective targeting of specific brain regions are critical to success of these devices. Development of directional electrodes that activate smaller volumes of brain tissue requires electrodes to operate safely with higher charge densities. Coatings such as conductive hydrogels (CHs) provide lower impedances and higher charge injection limits (CILs) than standard platinum electrodes and support safer application of smaller electrode sizes. The aim of this study was to examine the chronic in vivo performance of a new low swelling CH coating that supports higher safe charge densities than traditional platinum electrodes. A range of hydrogel blends were engineered and their swelling and electrical performance compared. Electrochemical performance and stability of high and low swelling formulations were compared during insertion into a model brain in vitro and the formulation with lower swelling characteristics was chosen for the in vivo study. CH-coated or uncoated Pt electrode arrays were implanted into the brains of 14 rats, and their electrochemical performance was tested weekly for 8 weeks. Tissue response and neural survival was assessed histologically following electrode array removal. CH coating resulted in significantly lower voltage transient impedance, higher CIL, lower electrochemical impedance spectroscopy, and higher charge storage capacity compared to uncoated Pt electrodes in vivo , and this advantage was maintained over the 8-week implantation. There was no significant difference in evoked potential thresholds, signal-to-noise ratio, tissue response or neural survival between CH-coated and uncoated Pt groups. The significant electrochemical advantage and stability of CH coating in the brain supports the suitability of this coating technology for future development of smaller, higher fidelity electrode arrays with higher charge density requirement., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hyakumura, Aregueta-Robles, Duan, Villalobos, Adams, Poole-Warren and Fallon.)

COVID-19 has had a negative impact on family caregivers, whether the care receivers lived with the caregiver, in a separate community home, in supportive living, or in long-term care. This qualitative study examines the points of view of family caregivers who care in diverse settings. Family caregivers were asked to describe what could have been done to support them during the COVID-19 pandemic and to suggest supports they need in the future as the pandemic wanes. Thorne's interpretive qualitative methodology was employed to examine current caregiver concerns. Thirty-two family caregivers participated. Family caregivers thought the under-resourced, continuing care system delayed pandemic planning, and that silos in health and community systems made caregiving more difficult. Family caregivers want their roles to be recognized in policy, and they cite the need for improvements in communication and navigation. The growth in demand for family caregivers and their contributions to the healthcare system make it critical that the family caregiver role be recognized in policy, funding, and practice.

Competing Interests: We declare no competing interests.

Background: We evaluated the efficacy and safety of roxadustat versus epoetin alfa for the treatment of chronic kidney disease-related anemia in patients new to dialysis., Methods: HIMALAYAS was a Phase 3, open-label, epoetin alfa-controlled trial. Eligible adults were incident to hemodialysis/peritoneal dialysis for 2 weeks to ≤4 months prior to randomization and had mean hemoglobin (Hb) ≤10.0 g/dL. Primary endpoints were mean Hb (g/dL) change from baseline averaged over Weeks 28-52 regardless of rescue therapy [non-inferiority criterion: lower limit of 95% confidence interval (CI) for treatment difference >-0.75] and percentage of patients achieving an Hb response between Weeks 1 and 24 censored for rescue therapy (non-inferiority margin for between-group difference -15%). Adverse events were monitored., Results: The intent-to-treat population included patients randomized to roxadustat (n = 522) or epoetin alfa (n = 521). Mean (standard deviation) Hb changes from baseline averaged over Weeks 28-52 were 2.57 (1.27) and 2.36 (1.21) in the roxadustat and epoetin alfa groups. Roxadustat was non-inferior [least squares mean difference: 0.18 (95% CI 0.08, 0.29)] to epoetin alfa. Percentages of patients with an Hb response were 88.2% and 84.4% in the roxadustat and epoetin alfa groups, respectively. Roxadustat was non-inferior to epoetin alfa [treatment-group difference 3.5% (95% CI -0.7%, 7.7%)]. Adverse event rates were comparable between treatment groups., Conclusions: Roxadustat was efficacious for correcting and maintaining Hb levels compared with epoetin alfa. Roxadustat had an acceptable safety profile., (© The Author(s) 2021. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background: Tonsillopharyngitis is a common presentation to paediatric emergency departments (PEDs). FeverPAIN (FP) and Centor scoring systems are recommended in the UK to help delineate bacterial aetiology, despite being primarily evidenced in adult populations. We investigate how the use of FP or Centor compares to actual clinician practice in guiding antibiotic prescription rates in PED. We establish current national practice in English PEDs., Methods: We performed a retrospective cohort study of tonsillopharyngitis presentations to a tertiary PED in January-February 2020. Investigators retrospectively assigned each patient FP and Centor scores using documented symptoms. We compared antibiotic prescription rates guided by FP/Centor against the actual rate prescribed by clinicians, and assessed agreement between these strategies using kappa analysis. We contacted 153 English emergency departments to establish national practice., Results: We identified 632 consecutive patients aged 6 months to 15 years. Actual clinician-prescribed antibiotics numbered 116 (18.4%). Prescriptions predicted by FP score numbered 124 (19.6%) and Centor 112 (17.7%). Kappa (K) analysis indicated only moderate agreement between clinician choice versus FP (K=0.434) and clinician choice versus Centor (K=0.476). This was similar for cohorts aged under and over 3 years.National practice was reportedly heterogeneous, with 70 emergency departments (45.8%) not employing a specific system., Conclusion: Current guidance is variably interpreted and inconsistently implemented in paediatric populations. FeverPAIN and Centor scoring systems may not rationalise antibiotics as much as previously reported compared with judicious clinician practice. Producing clear paediatric-specific national guidelines, especially for under-5s who are omitted from NICE sore throat guidance, may help further rationalise and standardise antibiotic use in paediatric tonsillopharyngitis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

This study explored family caregivers' use of technology to care for people with dementia living at home. Three questions were pursued: (1) what are the important, unmet needs of family caregivers, (2) how do they use technologies to assist in care tasks, and (3) what do health care providers know about caregivers' needs and technology use? Two comprehensive surveys were developed to answer these questions: one for family caregivers (n = 33), and one for health care providers (n = 60). Descriptive and quantitative analyses showed that caregivers' important, unmet needs were in the domains of information, formal services, and emotional support. Caregivers make limited use of technology but believe in its potential usefulness. Health care providers agree that technology is useful in dementia care; however, they underestimate caregivers' willingness to adopt technologies to communicate with providers. Findings prove caregiver willingness to use technology to support their care role and provide guidance regarding the caregiver needs that these technologies should address.

Objectives: Compared with the general population, people living with dementia have been unequivocally affected by the COVID-19 pandemic. However, there is a paucity of knowledge on the COVID-19 impact on people with dementia and their care partners. The objective of this scoping review was to synthesize the existing literature on the COVID-19 experiences of people with dementia and their care partners., Methods: Following Arksey and O'Malley's scoping review framework, we searched five electronic databases (Scopus, PubMed, CINAHL, EMBASE, and Web of Science) and an online search engine (Google Scholar). Inclusion criteria consisted of English-language articles focusing on the COVID-19 experiences of people with dementia and their care partners., Synthesis: Twenty-one articles met our inclusion criteria: six letters to the editor, seven commentaries, and eight original research studies. In the literature, five main themes were identified: (i) care partner fatigue and burnout; (ii) lack of access to services and supports; (iii) worsening neuropsychiatric symptoms and cognitive function; (iv) coping with COVID-19; and (v) the need for more evidence-informed research. Factors such as living alone, having advanced dementia, and the length of confinement were found to exacerbate the impact of COVID-19., Conclusion: Urgent action is needed to support people living with dementia and their care partners in the pandemic. With little access to supports and services, people with dementia and their care partners are currently at a point of crisis. Collaboration and more evidence-informed research are critical to reducing mortality and supporting people with dementia during the pandemic.

An increase in caregiver burden and a decrease in social support have both been identified as predictors of poor caregiver psychological distress. However, little is known about the role of these factors in coronary artery bypass graft (CABG) caregivers. The purpose of this study was to investigate whether change in perceived social support from pre to post surgery mediated the relationship between change in caregiver burden and caregiver depressive symptoms and subjective well-being post surgery. A sample of 101 caregivers of elective CABG patients were assessed 28 days before and 62 days after patients' surgery. Caregivers completed the Oberst Burden Scale, the Enhancing Recovery in Coronary Heart Disease (ENRICHD) Social Support Instrument, the Beck Depression Inventory, and the Control, Autonomy, Self-Realisation, and Pleasure (CASP-19) scale. Simple mediation analyses showed that change in social support significantly mediated both the relationship between change in caregiver burden and post-surgery depressive symptoms (unstandardised β = 0.041, 95% CI (0.005, 0.112)) and the relationship between change in caregiver burden and post-surgery subjective well-being (unstandardised β = 0.071, 95% CI (0.001, 0.200)). Psychological interventions aimed at the CABG caregiver population should promote social support to deal with the increase of caregivers' tasks and demands after the patients' surgery.

Introduction: The COVID-19 pandemic prompted the development and implementation of hundreds of clinical trials across the USA. The Trial Innovation Network (TIN), funded by the National Center for Advancing Translational Sciences, was an established clinical research network that pivoted to respond to the pandemic., Methods: The TIN's three Trial Innovation Centers, Recruitment Innovation Center, and 66 Clinical and Translational Science Award Hub institutions, collaborated to adapt to the pandemic's rapidly changing landscape, playing central roles in the planning and execution of pivotal studies addressing COVID-19. Our objective was to summarize the results of these collaborations and lessons learned., Results: The TIN provided 29 COVID-related consults between March 2020 and December 2020, including 6 trial participation expressions of interest and 8 community engagement studios from the Recruitment Innovation Center. Key lessons learned from these experiences include the benefits of leveraging an established infrastructure, innovations surrounding remote research activities, data harmonization and central safety reviews, and early community engagement and involvement., Conclusions: Our experience highlighted the benefits and challenges of a multi-institutional approach to clinical research during a pandemic., (© The Association for Clinical and Translational Science 2021.)

Background: Subjective well-being appears to be associated with reduced risk of type 2 diabetes (T2D). However, it is unknown whether this association is similar across different types of well-being. We examined the relationship between hedonic and eudaimonic well-being and incident T2D, and explored the role of sociodemographic, behavioural and clinical factors in these associations., Methods: We used data from 4134 diabetes-free participants from the English Longitudinal Study of Ageing (mean age =64.97). Enjoyment of life and purpose in life were assessed using items from the CASP-19 to reflect hedonic and eudaimonic well-being, respectively. Participants reported T2D diagnosis over 12 years. We used Cox proportional hazards regression analyses and also explored the percentage of association explained by different covariates., Results: Results revealed a protective role for enjoyment of life in T2D rate adjusting for sociodemographic (age, sex, wealth, ethnicity, marital status), behavioural (physical activity, smoking, alcohol consumption, body mass index) and clinical (hypertension, coronary heart disease and glycated haemoglobin) characteristics (HR =0.93, p=0.021, 95% CI (0.87, 0.99)). Sociodemographic, behavioural and clinical factors accounted for 27%, 27% and 18% of the association, respectively. The relationship between purpose in life and T2D was non-significant (adjusted HR =0.92, p=0.288, 95% CI (0.78, 1.08))., Conclusion: This study illustrates how the link between subjective well-being and T2D varies between well-being components. It also demonstrates that sociodemographic, behavioural and clinical factors partially explain this association. Intervention studies examining whether changes in enjoyment of life can help delay T2D onset are warranted., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The COVID-19 pandemic is affecting people with dementia in numerous ways. Nevertheless, there is a paucity of research on the COVID-19 impact on people with dementia and their care partners., Objective: Using Twitter, the purpose of this study is to understand the experiences of COVID-19 for people with dementia and their care partners., Methods: We collected tweets on COVID-19 and dementia using the GetOldTweets application in Python from February 15 to September 7, 2020. Thematic analysis was used to analyze the tweets., Results: From the 5063 tweets analyzed with line-by-line coding, we identified 4 main themes including (1) separation and loss; (2) COVID-19 confusion, despair, and abandonment; (3) stress and exhaustion exacerbation; and (4) unpaid sacrifices by formal care providers., Conclusions: There is an imminent need for governments to rethink using a one-size-fits-all response to COVID-19 policy and use a collaborative approach to support people with dementia. Collaboration and more evidence-informed research are essential to reducing COVID-19 mortality and improving the quality of life for people with dementia and their care partners., (©Juanita-Dawne Bacsu, Megan E O'Connell, Allison Cammer, Mahsa Azizi, Karl Grewal, Lisa Poole, Shoshana Green, Saskia Sivananthan, Raymond J Spiteri. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 03.02.2021.)

Aims: Diabetes-related distress is common in Type 2 Diabetes and is linked with poor diabetes control. However, mechanisms underlying this association are unclear. One pathway that could be involved is neuroendocrine dysfunction, as Type 2 Diabetes is associated with altered diurnal cortisol output. This study investigated the link between diabetes-related distress and diurnal cortisol output., Methods: 134 people with Type 2 Diabetes provided 5 cortisol samples over the course of a day. Multivariate linear regression models were used to assess whether overall and sub-domains of diabetes-related distress measured by the Diabetes Distress Scale, predicted cortisol parameters (waking cortisol, cortisol awakening response, cortisol slope and evening cortisol)., Results: Physician-related distress was associated with greater waking (B = 2.747, p = .015) and evening cortisol (B = 1.375, p = .014), and a blunted cortisol awakening response (B = -3.472, p = .038) adjusting for age, sex, income, body mass index, smoking and time of awakening. No associations were detected for overall distress, emotional, interpersonal or regimen distress., Conclusion: Physician-related distress was associated with alterations in daily cortisol output. Longitudinal research is required to understand how physician-related distress is associated with diurnal cortisol patterning over time., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objectives: In a longitudinal case-control observational study, we evaluated the benefits of a self-management programme for hands developed for patients with SSc., Methods: Patients with SSc included in the intervention group (IG) received a concise self-management programme with emphasis on hand exercises and were evaluated during 24 weeks regarding hand pain, hand function, range of motion, grip and tip and key pinch strength. Results were compared with a control group (CG) with no intervention using an analysis of variance for repeated measures with variables transformed into ranks (P ≤ 0.05). Effect sizes were calculated using Cohen's test., Results: Of 90 patients who were evaluated, seven were excluded at enrolment and 26 were excluded during the follow-up. Data from 57 subjects (IG 40, CG 17) were used for analysis. Groups were similar at baseline, except for the Scleroderma HAQ and tip and key pinch strength. Outcome improvements were noted only in the IG (P ≤ 0.05, large effect size). In the CG, variables did not change or had even worsened (hand grip strength and finger motion)., Conclusions: This self-management programme based on hand exercises for SSc resulted in pain reduction and hand function, strength and range of motion improvement. It can be a simple and useful intervention, especially when a regular rehabilitation programme is not available., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)