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Gabriel Izbicki,1,2 Valerie Teo,1,3 Jenifer Liang,4 Grant M Russell,5 Anne E Holland,6 Nicholas A Zwar,7 Billie Bonevski,8 Ajay Mahal,9 Paula Eustace,10 Eldho Paul,1 Kirsten Phillips,11 Sally Wilson,4,12 Johnson George,1,4 Michael J Abramson1 1School of Public Health & Preventive Medicine, Monash University, Melbourne, Australia; 2Shaare Zedek Medical Center and The Hebrew University Hadassah Medical School, Jerusalem, Israel; 3National Healthcare Group Polyclinics, Singapore; 4Centre For Medicine Use and Safety, Faculty of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Australia; 5Southern Academic Primary Care Research Unit, Department of General Practice, Monash University, Notting Hill, Australia; 6Discipline of Physiotherapy, La Trobe University and Alfred Health, Melbourne, Australia; 7Faculty of Health Sciences & Medicine, Bond University, Gold Coast, Australia; 8School of Medicine and Public Health, University of Newcastle, Callaghan, Australia; 9The Nossal Institute For Global Health, University of Melbourne, Melbourne, Australia; 10Eastern Melbourne PHN (EMPHN), Box Hill, Australia; 11Lung Foundation Australia (LFA), Milton, Australia; 12Department of Infrastructure Engineering, The University of Melbourne, Melbourne, AustraliaCorrespondence: Michael J AbramsonSchool of Public Health & Preventive Medicine, 553 St Kilda Road, Melbourne, VIC 3004, AustraliaTel +61 3 9903 0573Fax +61 3 9903 0556Email michael.abramson@monash.eduPurpose: Many older adults with a history of smoking and asthma develop clinical features of both asthma and COPD, an entity sometimes called asthma-COPD overlap (ACO). Patients with ACO may be at higher risk of poor health outcomes than those with asthma or COPD alone. However, understanding of ACO is limited in the primary care setting and more information is needed to better inform patient management. We aimed to compare the characteristics of patients with ACO or COPD in Australian general practices.Patients and methods: Data were from the RADICALS (Review of Airway Dysfunction and Interdisciplinary Community-based care of Adult Long-term Smokers) trial, an intervention study of an interdisciplinary community-based model of care. Baseline demographic and clinical characteristics, pre- and post-bronchodilator spirometry, dyspnoea and St. George’s Respiratory Questionnaire scores were compared between 60 ACO patients and 212 with COPD alone.Results: Pre-bronchodilator Forced Expiratory Volume in 1 second (mean±SD 58.4±14.3 vs 67.5±20.1% predicted) and Forced Vital Capacity (mean 82.1±16.9 v 91.9±17.2% predicted) were significantly lower in the ACO group (p

Mark F Harris,1 Jenny Advocat,2 Benjamin F Crabtree,3 Jean-Frederic Levesque,1,4 William L Miller,5 Jane M Gunn,6 William Hogg,7 Cathie M Scott,8 Sabrina M Chase,9 Lisa Halma,10 Grant M Russell11 1Center for Primary Health Care and Equity, University of New South Wales, Sydney, NSW, 2Southern Academic Primary Care Research Unit, School of Primary Health Care, Monash University, Notting Hill, VIC, Australia; 3Department of Family Medicine and Community Health, Rutgers Robert Wood Johnson Medical School, New Brunswick, NJ, USA; 4Bureau of Health Information, NSW Government, Sydney, NSW, Australia; 5Department of Family Medicine, Lehigh Valley Health Network, Allentown, PA, USA; 6Department of General Practice, The University of Melbourne, Melbourne, VIC, Australia; 7The CT Lamont Primary Care Research Center, The University of Ottawa, Ottawa, ON, 8Alberta Centre for Child, Family, and Community Research, University of Calgary, AB, Canada; 9Rutgers University, Rutgers School of Nursing, Rutgers, NJ, USA; 10Alberta Health Services, Lethbridge, AB, Canada; 11School of Primary Health Care, Monash University, Notting Hill, VIC, Australia Context: A key aim of reforms to primary health care (PHC) in many countries has been to enhance interprofessional teamwork. However, the impact of these changes on practitioners has not been well understood.Objective: To assess the impact of reform policies and interventions that have aimed to create or enhance teamwork on professional communication relationships, roles, and work satisfaction in PHC practices.Design: Collaborative synthesis of 12 mixed methods studies.Setting: Primary care practices undergoing transformational change in three countries: Australia, Canada, and the USA, including three Canadian provinces (Alberta, Ontario, and Quebec).Methods: We conducted a synthesis and secondary analysis of 12 qualitative and quantitative studies conducted by the authors in order to understand the impacts and how they were influenced by local context.Results: There was a diverse range of complex reforms seeking to foster interprofessional teamwork in the care of patients with chronic disease. The impact on communication and relationships between different professional groups, the roles of nursing and allied health services, and the expressed satisfaction of PHC providers with their work varied more within than between jurisdictions. These variations were associated with local contextual factors such as the size, power dynamics, leadership, and physical environment of the practice. Unintended consequences included deterioration of the work satisfaction of some team members and conflict between medical and nonmedical professional groups.Conclusion: The variation in impacts can be understood to have arisen from the complexity of interprofessional dynamics at the practice level. The same characteristic could have both positive and negative influence on different aspects (eg, larger practice may have less capacity for adoption but more capacity to support interprofessional practice). Thus, the impacts are not entirely predictable and need to be monitored, and so that interventions can be adapted at the local level.Keywords: interprofessional care, primary health care, teamwork, research synthesis

Background: Primary care is often described as slow to change. But conceptualized through complexity theory, primary care is continually changing in unpredictable, non-linear ways through self-organization processes. Self-organization has proven hard to study directly. We aimed to develop a methodology to study self-organization and describe how a primary care clinic self-organizes over time., Methodology: We completed a virtual case study of an urban primary care clinic from May-Nov 2021, applying methodological insights from actor-network theory to examine the complexity theory concept of self-organization. We chose to focus our attention on self-organization activities that alter organizational routines. Data included fieldnotes of observed team meetings, document collection, interviews with clinic members, and notes from brief weekly discussions to detect actions to change clinical and administrative routines. Adapting schema analysis, we described changes to different organizational routines chronologically, then explored intersecting changes. We sought feedback on results from the participating clinic., Findings: Re-establishing equilibrium remained challenging well into the COVID-19 pandemic. The primary care clinic continued to self-organize in response to changing health policies, unintended consequences of earlier adaptations, staff changes, and clinical care initiatives. Physical space, technologies, external and internal policies, guidelines, and clinic members all influenced self-organization. Changing one created ripple effects, sometimes generating new, unanticipated problems. Member checking confirmed we captured most of the changes to organizational routines during the case study period., Conclusions: Through insights from actor-network theory, applied to studying actions taken that alter organizational routines, it is possible to operationalize the theoretical construct of self-organization. Our methodology illuminates the primary care clinic as a continually changing entity with co-existing and intersecting processes of self-organization in response to varied change pressures., (© 2024. The Author(s).)

Background: Sleep disturbances are a potentially modifiable risk factor for neurodegenerative dementia secondary to Alzheimer disease (AD) and Lewy body disease (LBD). Therefore, we need to identify the best methods to study sleep in this population., Objective: This study will assess the feasibility and acceptability of various wearable devices, smart devices, and remote study tasks in sleep and cognition research for people with AD and LBD., Methods: We will deliver a feasibility and acceptability study alongside a prospective observational cohort study assessing sleep and cognition longitudinally in the home environment. Adults aged older than 50 years who were diagnosed with mild to moderate dementia or mild cognitive impairment (MCI) due to probable AD or LBD and age-matched controls will be eligible. Exclusion criteria include lack of capacity to consent to research, other causes of MCI or dementia, and clinically significant sleep disorders. Participants will complete a cognitive assessment and questionnaires with a researcher and receive training and instructions for at-home study tasks across 8 weeks. At-home study tasks include remote sleep assessments using wearable devices (electroencephalography headband and actigraphy watch), app-based sleep diaries, online cognitive assessments, and saliva samples for melatonin- and cortisol-derived circadian markers. Feasibility outcomes will be assessed relating to recruitment and retention, data completeness, data quality, and support required. Feedback on acceptability and usability will be collected throughout the study period and end-of-study interviews will be analyzed using thematic analysis., Results: Recruitment started in February 2022. Data collection is ongoing, with final data expected in February 2024 and data analysis and publication of findings scheduled for the summer of 2024., Conclusions: This study will allow us to assess if remote testing using smart devices and wearable technology is a viable alternative to traditional sleep measurements, such as polysomnography and questionnaires, in older adults with and without MCI or dementia due to AD or LBD. Understanding participant experience and the barriers and facilitators to technology use for research purposes and remote research in this population will assist with the development of, recruitment to, and retention within future research projects studying sleep and cognition outside of the clinic or laboratory., International Registered Report Identifier (irrid): DERR1-10.2196/52652., (©Victoria Grace Gabb, Jonathan Blackman, Hamish Duncan Morrison, Bijetri Biswas, Haoxuan Li, Nicholas Turner, Georgina M Russell, Rosemary Greenwood, Amy Jolly, William Trender, Adam Hampshire, Alan Whone, Elizabeth Coulthard. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 22.03.2024.)

Background: Primary aldosteronism (PA) is a common but underdiagnosed cause of hypertension. Many patients experience preventable end-organ injury due to delayed or missed diagnosis but data on the experience of patients are limited., Methods: We evaluated the lived experience of PA and determines factors associated with diagnostic delay through an international anonymous online cross-sectional survey, codesigned by researchers and PA consumers. We distributed the survey through academic medical centers, Amazon Mechanical Turk, Twitter, PA patient advocacy groups, and hypertension support groups on Facebook between March 21 and June 5, 2022., Results: Of 684 eligible respondents, 66.5% were women. Diagnostic delay (defined as ≥5 years between the diagnosis of hypertension and PA) was reported in 35.6%. Delay was more likely in women than in men (odds ratio, 1.55 [95% CI, 1.10-2.20]) and respondents with ≥3 comorbidities versus none (odds ratio, 1.77 [95% CI, 1.05-3.02]), ≥10 symptoms versus none (odds ratio, 2.73 [95% CI, 1.74-4.44]), and on ≥4 antihypertensive medications versus none (odds ratio, 18.23 [95% CI, 6.24-77.72]). Three-quarters of patients (74.4%) experienced reduced symptom burden following targeted PA treatment. Quality of life improved in 62.3% of patients, and greater improvement was associated with being a woman (odds ratio, 1.42, [95% CI, 1.02-1.97]), receiving adrenalectomy (odds ratio, 2.36 [95% CI, 1.67-3.35]), and taking fewer antihypertensive medications following diagnosis (odds ratio, 5.28 [95% CI, 3.55-7.90])., Conclusions: One-third of patients with PA experienced prolonged diagnostic delays. Targeted treatment led to reduced symptom burden and improved quality of life. Gender differences in diagnostic delay and symptom burden are prominent. These findings suggest that routine screening for PA at the onset of hypertension may reduce diagnostic delay and facilitate timely diagnosis., Competing Interests: Disclosures None.

Primary care (PC) is a unique clinical specialty and research discipline with its own perspectives and methods. Research in this field uses varied research methods and study designs to investigate myriad topics. The diversity of PC presents challenges for reporting, and despite the proliferation of reporting guidelines, none focuses specifically on the needs of PC. The Consensus Reporting Items for Studies in Primary Care (CRISP) Checklist guides reporting of PC research to include the information needed by the diverse PC community, including practitioners, patients, and communities. CRISP complements current guidelines to enhance the reporting, dissemination, and application of PC research findings and results. Prior CRISP studies documented opportunities to improve research reporting in this field. Our surveys of the international, interdisciplinary, and interprofessional PC community identified essential items to include in PC research reports. A 2-round Delphi study identified a consensus list of items considered necessary. The CRISP Checklist contains 24 items that describe the research team, patients, study participants, health conditions, clinical encounters, care teams, interventions, study measures, settings of care, and implementation of findings/results in PC. Not every item applies to every study design or topic. The CRISP guidelines inform the design and reporting of (1) studies done by PC researchers, (2) studies done by other investigators in PC populations and settings, and (3) studies intended for application in PC practice. Improved reporting of the context of the clinical services and the process of research is critical to interpreting study findings/results and applying them to diverse populations and varied settings in PC. Annals "Online First" article., (© 2023 Annals of Family Medicine, Inc.)

Photopolymerization and photoprocessing are core technologies for molding and tuning polymer materials. However, they are incompatible with single materials owing to their contradictory photoreactivity. Herein, an acid-induced photocleavable crosslinker, a platinum-acetylide complex covered by permethylated cyclodextrins, enables the fabrication of photoprocessable materials via photopolymerization with N-(2-hydroxyethyl)acrylamide. The polymer networks are molded by 365 nm irradiation as well as softened and degraded by a cooperative reaction with HCl as an acidic additive under 365 nm UV light, or 470 nm visible light in the presence of a photosensitizer. Moreover, the crosslinker is applied to a photoadhesive triggered by 365 nm irradiation. The adhesion is detachable on-demand through acid-induced photodegradation with the same wavelength and intensity of irradiation. Thus, acid-induced photocleavage allows the integration of light-induced molding and processing under various lights of various wavelengths, opening up new strategies for polymer technologies., (© 2023 The Authors. Angewandte Chemie International Edition published by Wiley-VCH GmbH.)

Objectives: To assess the mental health and wellbeing of health and aged care workers in Australia during the second and third years of the coronavirus disease 2019 (COVID-19) pandemic, overall and by occupation group., Design, Setting, Participants: Longitudinal cohort study of health and aged care workers (ambulance, hospitals, primary care, residential aged care) in Victoria: May-July 2021 (survey 1), October-December 2021 (survey 2), and May-June 2022 (survey 3)., Main Outcome Measures: Proportions of respondents (adjusted for age, gender, socio-economic status) reporting moderate to severe symptoms of depression (Patient Health Questionnaire-9, PHQ-9), anxiety (Generalized Anxiety Disorder scale, GAD-7), or post-traumatic stress (Impact of Event Scale-6, IES-6), burnout (abbreviated Maslach Burnout Inventory, aMBI), or high optimism (10-point visual analogue scale); mean scores (adjusted for age, gender, socio-economic status) for wellbeing (Personal Wellbeing Index-Adult, PWI-A) and resilience (Connor Davidson Resilience Scale 2, CD-RISC-2)., Results: A total of 1667 people responded to at least one survey (survey 1, 989; survey 2, 1153; survey 3, 993; response rate, 3.3%). Overall, 1211 survey responses were from women (72.6%); most respondents were hospital workers (1289, 77.3%) or ambulance staff (315, 18.9%). The adjusted proportions of respondents who reported moderate to severe symptoms of depression (survey 1, 16.4%; survey 2, 22.6%; survey 3, 19.2%), anxiety (survey 1, 8.8%; survey 2, 16.0%; survey 3, 11.0%), or post-traumatic stress (survey 1, 14.6%; survey 2, 35.1%; survey 3, 14.9%) were each largest for survey 2. The adjusted proportions of participants who reported moderate to severe symptoms of burnout were higher in surveys 2 and 3 than in survey 1, and the proportions who reported high optimism were smaller in surveys 2 and 3 than in survey 1. Adjusted mean scores for wellbeing and resilience were similar at surveys 2 and 3 and lower than at survey 1. The magnitude but not the patterns of change differed by occupation group., Conclusion: Burnout was more frequently reported and mean wellbeing and resilience scores were lower in mid-2022 than in mid-2021 for Victorian health and aged care workers who participated in our study. Evidence-based mental health and wellbeing programs for workers in health care organisations are needed., Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12621000533897 (observational study; retrospective)., (© 2023 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

The characteristic endogenous circadian rhythm of plasma glucocorticoid concentrations is made up from an underlying ultradian pulsatile secretory pattern. Recent evidence has indicated that this ultradian cortisol pulsatility is crucial for normal emotional response in man. In this study, we investigate the anatomical transcriptional and cell type signature of brain regions sensitive to a loss of ultradian rhythmicity in the context of emotional processing. We combine human cell type and transcriptomic atlas data of high spatial resolution with functional magnetic resonance imaging (fMRI) data. We show that the loss of cortisol ultradian rhythm alters emotional processing response in cortical brain areas that are characterized by transcriptional and cellular profiles of GABAergic function. We find that two previously identified key components of rapid non-genomic GC signaling - the ANXA1 gene and retrograde endocannabinoid signaling - show most significant differential expression (q = 3.99e -10 ) and enrichment (fold enrichment = 5.56, q = 9.09e -4 ). Our results further indicate that specific cell types, including a specific NPY-expressing GABAergic neuronal cell type, and specific G protein signaling cascades underly the cerebral effects of a loss of ultradian cortisol rhythm. Our results provide a biological mechanistic underpinning of our fMRI findings, indicating specific cell types and cascades as a target for manipulation in future experimental studies., Competing Interests: 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., (© 2023 The Authors.)

A coumarin derivative bearing a [1]rotaxane structure with permethylated α-cyclodextrins suppressed unwanted solvation-induced effects and increased luminescent quantum yields in medium- and high-polarity solvents. The non-radiative decay was suppressed by the twist in the π-conjugated system and the radiative decay was enhanced by the suppression of the polarity-induced structural changes.

Objective: To assess the identification of primary aldosteronism (PA) in newly diagnosed, treatment-naïve patients with hypertension by screening in primary care., Design: Prospective study., Setting: General practices in the South Eastern Melbourne Primary Health Network with at least three general practitioners and general practices elsewhere in Victoria that had referred patients to the Endocrine Hypertension Clinic at Monash Health, 2017-2020., Participants: Adults (18-80 years) with newly diagnosed hypertension (measurements of systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg on at least two occasions) and not taking antihypertensive medications were screened for PA by assessing their aldosterone-to-renin ratio (ARR). Participants with two ARR values exceeding 70 pmol/mU underwent saline suppression testing at the Endocrine Hypertension Service (Monash Health) to confirm the diagnosis of PA., Main Outcome Measures: Prevalence of PA (number of patients with confirmed PA divided by number screened)., Results: Sixty-two of 247 screened participants had elevated ARR values on screening (25%); for 35 people (14%; 95% CI, 10-19%), PA was confirmed by saline suppression testing. Baseline characteristics (mean age, sex distribution, median baseline blood pressure levels, and serum potassium concentration) were similar for people with or without PA., Conclusion: PA was diagnosed in 14% of patients with newly diagnosed hypertension screened by GPs, indicating a potential role for GPs in the early detection of an important form of secondary hypertension for which specific therapies are available., (© 2022 AMPCo Pty Ltd.)

Objectives: To examine whether primary care outreach facilitation improves the quality of care for general practice patients from refugee backgrounds., Design: Pragmatic, cluster randomised controlled trial, with stepped wedge allocation to early or late intervention groups., Setting, Participants: 31 general practices in three metropolitan areas of Sydney and Melbourne with high levels of refugee resettlement, November 2017 - August 2019., Intervention: Trained facilitators made three visits to practices over six months, using structured action plans to help practice teams optimise routines of refugee care., Major Outcome Measure: Change in proportion of patients from refugee backgrounds with documented health assessments (Medicare billing). Secondary outcomes were refugee status recording, interpreter use, and clinician-perceived difficulty in referring patients to appropriate dental, social, settlement, and mental health services., Results: Our sample comprised 14 633 patients. The intervention was associated with an increase in the proportion of patients with Medicare-billed health assessments during the preceding six months, from 19.1% (95% CI, 18.6-19.5%) to 27.3% (95% CI, 26.7-27.9%; odds ratio, 1.88; 95% CI, 1.42-2.50). The impact of the intervention was greater in smaller practices, practices with larger proportions of patients from refugee backgrounds, recent training in refugee health care, or higher baseline provision of health assessments for such patients. There was no impact on refugee status recording, interpreter use increased modestly, and reported difficulties in refugee-specific referrals to social, settlement and dental services were reduced., Conclusions: Low intensity practice facilitation may improve some aspects of primary care for people from refugee backgrounds. Facilitators employed by local health services could support integrated approaches to enhancing the quality of primary care for this vulnerable population., Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12618001970235 (retrospective)., (© 2021 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

In the context of glucocorticoid (GC) therapeutics, recent studies have utilised a subcutaneous hydrocortisone (HC) infusion pump programmed to deliver multiple HC pulses throughout the day, with the purpose of restoring normal circadian and ultradian GC rhythmicity. A key challenge for the advancement of novel HC replacement therapies is the calibration of infusion pumps against cortisol levels measured in blood. However, repeated blood sampling sessions are enormously labour-intensive for both examiners and examinees. These sessions also have a cost, are time consuming and are occasionally unfeasible. To address this, we developed a pharmacokinetic model approximating the values of plasma cortisol levels at any point of the day from a limited number of plasma cortisol measurements. The model was validated using the plasma cortisol profiles of 9 subjects with disrupted endogenous GC synthetic capacity. The model accurately predicted plasma cortisol levels (mean absolute percentage error of 14%) when only four plasma cortisol measurements were provided. Although our model did not predict GC dynamics when HC was administered in a way other than subcutaneously or in individuals whose endogenous capacity to produce GCs is intact, it was found to successfully be used to support clinical trials (or practice) involving subcutaneous HC delivery in patients with reduced endogenous capacity to synthesize GCs.

Purpose: To assess how primary care practitioners use reports of general health care (GHC) and primary care (PC) research and how well reports deliver what they need to inform clinical practice., Methods: International, interprofessional online survey, 2019, of primary care clinicians who see patients at least half time. Respondents used frequency scales to report how often they access both GHC and PC research and how frequently reports meet needs. Free-text short comments recorded comments and suggestions., Results: Survey yielded 252 respondents across 29 nations, 55% (121) women, including 88% (195) physicians, nurses 5% (11), and physician assistants 3% (7). Practitioners read research reports frequently but find they usually fail to meet their needs. For PC research, 33% (77) accessed original reports in academic journals weekly or daily, and 36% found reports meet needs "frequently" or "always." They access reports of GHC research slightly more often but find them somewhat less useful., Conclusions: PC practitioners access original research in academic journals frequently but find reports meet information needs less than half the time. PC research reflects the unique PC setting and so reporting has distinct focus, needs, and challenges. Practitioners desire improved reporting of study context, interventions, relationships, generalizability, and implementation., Competing Interests: Conflict of interest: None. Conflict of interest: None., (© Copyright 2021 by the American Board of Family Medicine.)

Objective: To investigate whether integrating pharmacists into general practices reduces the number of unplanned re-admissions of patients recently discharged from hospital., Design, Setting: Stepped wedge, cluster randomised trial in 14 general practices in southeast Queensland., Participants: Adults discharged from one of seven study hospitals during the seven days preceding recruitment (22 May 2017 - 14 March 2018) and prescribed five or more long term medicines, or having a primary discharge diagnosis of congestive heart failure or exacerbation of chronic obstructive pulmonary disease., Intervention: Comprehensive face-to-face medicine management consultation with an integrated practice pharmacist within seven days of discharge, followed by a consultation with their general practitioner and further pharmacist consultations as needed., Major Outcomes: Rates of unplanned, all-cause hospital re-admissions and emergency department (ED) presentations 12 months after hospital discharge; incremental net difference in overall costs., Results: By 12 months, there had been 282 re-admissions among 177 control patients (incidence rate [IR], 1.65 per person-year) and 136 among 129 intervention patients (IR, 1.09 per person-year; fully adjusted IR ratio [IRR], 0.79; 95% CI, 0.52-1.18). ED presentation incidence (fully adjusted IRR, 0.46; 95% CI, 0.22-0.94) and combined re-admission and ED presentation incidence (fully adjusted IRR, 0.69; 95% CI, 0.48-0.99) were significantly lower for intervention patients. The estimated incremental net cost benefit of the intervention was $5072 per patient, with a benefit-cost ratio of 31:1., Conclusion: A collaborative pharmacist-GP model of post-hospital discharge medicines management can reduce the incidence of hospital re-admissions and ED presentations, achieving substantial cost savings to the health system., Trial Registration: Australian New Zealand Clinical Trials Registry, ACTRN12616001627448 (prospective)., (© 2021 AMPCo Pty Ltd.)

Adrenal glucocorticoid secretion into the systematic circulation is characterised by a complex rhythm, composed of the diurnal variation, formed by changes in pulse amplitude of an underlying ultradian rhythm of short duration hormonal pulses. To elucidate the potential neurobiological significance of glucocorticoid pulsatility in man, we have conducted a randomised, double-blind, placebo-controlled, three-way crossover clinical trial on 15 healthy volunteers, investigating the impact of different glucocorticoid rhythms on measures of mood and neural activity under resting conditions by recruiting functional neuroimaging, computerised behavioural tests and ecological momentary assessments. Endogenous glucocorticoid biosynthesis was pharmacologically suppressed, and plasma levels of corticosteroid restored by hydrocortisone replacement in three different regimes, either mimicking the normal ultradian and circadian profile of the hormone, or retaining the normal circadian but abolishing the ultradian rhythm of the hormone, or by our current best oral replacement regime which results in a suboptimal circadian and ultradian rhythm. Our results indicate that changes in the temporal mode of glucocorticoid replacement impact (i) the morning levels of self-perceived vigour, fatigue and concentration, (ii) the diurnal pattern of mood variation, (iii) the within-network functional connectivity of various large-scale resting state networks of the human brain, (iv) the functional connectivity of the default-mode, salience and executive control networks with glucocorticoid-sensitive nodes of the corticolimbic system, and (v) the functional relationship between mood variation and underlying neural networks. The findings indicate that the pattern of the ultradian glucocorticoid rhythm could affect cognitive psychophysiology under non-stressful conditions and opens new pathways for our understanding on the neuropsychological effects of cortisol pulsatility with relevance to the goal of optimising glucocorticoid replacement strategies., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To assess opportunities to improve reporting of primary care (PC) research to better meet the needs of its varied users., Methods: International, interprofessional online survey of PC researchers and users, 2018 to 2019. Respondents used Likert scales to rate frequency of difficulties in interpreting, synthesizing, and applying PC research reports. Free-text short answers were categorized by template analysis to record experiences, concerns, and suggestions. Areas of need were checked across existing reporting guidelines., Results: Survey yielded 255 respondents across 24 nations, including 138 women (54.1%), 169 physicians (60%), 32 scientists (11%), 20 educators (7%), and 18 public health professionals (6%). Overall, 37.4% indicated difficulties using PC research reports "50% or more of the time." The most common problems were synthesizing findings (58%) and assessing generalizability (42%). Difficulty was reported by 49% for qualitative, 46% for mixed methods, and 38% for observational research. Most users wanted richer reporting of theoretical foundation (53.7%); teams, roles, and organization of care (53.4%); and patient involvement in the research process (52.7%). Few reported difficulties with ethics or disclosure of funding or conflicts. Free-text answers described special challenges in reporting PC research: context of clinical care and setting; practical details of interventions; patient-clinician and team relationships; and generalizability, applicability and impact in the great variety of PC settings. Cross-check showed that few current reporting guidelines focus on these needs., Conclusions: Opportunities exist to improve the reporting of PC research to make it more useful for its many users, suggesting a role for a PC research reporting guideline., Competing Interests: Conflict of interest: None., (© Copyright 2021 by the American Board of Family Medicine.)

Context: In humans, approximately 95% of circulating cortisol is bound to corticosteroid-binding globulin and albumin. It is only the free fraction that is biologically active and can activate signaling pathways via glucocorticoid hormone receptors in cells. Microdialysis is a well-established technique that enables the sampling of molecules in different compartments of the body, including extracellular fluid. This is the first study validating a rapid sampling microdialysis method measuring free cortisol in the subcutaneous and blood compartments of healthy volunteers., Methods: Healthy nonsmoking volunteers (42 men, aged 18-24 years; body mass index 18-25 kg/m2) received placebo (saline), 250 μg Synacthen, or 1 mg dexamethasone with 10-minute sampling to measure total and free cortisol (subcutaneous, intravenous, and saliva) for an hour before and 4 hours after administration., Results: Following stimulation by Synacthen, total serum cortisol and free cortisol in both compartments rose significantly, achieving and maintaining maximum levels between 2 and 3 hours following the stimulus. A decline in cortisol levels was evident after the administration of dexamethasone or placebo, but there was a clear pulsatile activity around lunchtime in the latter group, which was prominent in the blood compartment (total and free cortisol). There was good correlation between serum total and free cortisol (subcutaneous and intravenous) in the Synacthen and dexamethasone groups with no significant delay (less than 5 minutes) between total and free cortisol., Conclusions: This seminal study demonstrated the dynamic responses of total blood cortisol and microdialysis derived free cortisol in blood, subcutaneous tissue, and saliva in men., (© Endocrine Society 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: The pituitary-adrenal axis had historically been considered a representative model for circadian rhythms. A recently developed portable collection device has provided the opportunity to evaluate free cortisol profiles using the microdialysis approach in individuals free to conduct their day-to-day activities in their own surroundings., Methods: Two separate experiments were conducted in healthy male volunteers. The total and subcutaneous (SC) free cortisol levels were measured at 10-minute intervals for a 24-hour period in one experiment, and the SC free cortisol levels were measured at 20-minute interval for 72 consecutive hours in free-living individuals in the second experiment., Results: The characteristic circadian rhythm was evident in both serum total and SC free cortisol, with the lowest levels achieved and maintained in the hours surrounding sleep onset and the peak levels occurring in every individual around waking. In all free-living individuals, the circadian rhythm was consistent across the 72-hour period, despite a wide range of activities. All the participants also showed increased cortisol after the consumption of lunch. The lowest levels during all 24-hour periods were observed during the hours after lights off, at the onset of sleep., Conclusions: To the best of our knowledge, the present study is the first to report up to three consecutive 24-hour measurements of SC free cortisol in healthy individuals. We believe our study is a landmark study that paves the way for ambulatory monitoring of free cortisol profiles continuously for a period of 72 hours in free-living individuals performing their day-to-day activities whether healthy or with diseases involving the hypothalamic-pituitary-adrenal axis., (Copyright © 2019 Endocrine Society.)

Glucocorticoid neurodynamics are the most crucial determinant of the hormonal effects in the mammalian brain, and depend on multiple parallel receptor and enzymatic systems, responsible for effectively binding with the hormone (and mediating its downstream molecular effects) and altering the local glucocorticoid content (by adding, removing or degrading glucocorticoids), respectively. In this study, we combined different computational tools to extract, process and visualize the gene expression data of 25 genes across 96 regions of the adult C57Bl/6J mouse brain, implicated in glucocorticoid neurodynamics. These data derive from the anatomic gene expression atlas of the adult mouse brain of the Allen Institute for Brain Science, captured via the in situ hybridization technique. A careful interrogation of the datasets referring to these 25 genes of interest, based on a targeted, prior knowledge-driven approach, revealed useful pieces of information on spatial differences in the glucocorticoid-sensitive receptors, in the regional capacity for local glucocorticoid biosynthesis, excretion, conversion to other biologically active forms and degradation. These data support the importance of the corticolimbic system of the mammalian brain in mediating glucocorticoid effects, and particularly hippocampus, as well as the need for intensifying the research efforts on the hormonal role in sensory processing, executive control function, its interplay with brain-derived neurotrophic factor and the molecular basis for the regional susceptibility of the brain to states of prolonged high hormonal levels. Future work could expand this methodology by exploiting Allen Institute's databases from other species, introducing complex tools of data analysis and combined analysis of different sources of biological datasets., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Glucocorticoids are a class of systematically secreted hormones, vital for mammalian life, which are intensively investigated for more than 80 years. They regulate multiple body processes like metabolism, fluid homeostasis, immune and stress system responsivity, as well as brain function. Glucocorticoids have a complex rhythm by which they are released to circulation from the adrenal cortex. The hormone exhibits a circadian variation, with high hormonal levels being secreted just prior and during the active part of the day, and progressively lower and lower amounts being released during the inactive part of it. Underlying this diurnal variation there is a more dynamic, ultradian rhythm composed of frequent episodes of glucocorticoid secretion (hormonal pulses). Accumulating evidence from observational, in silico, in vitro and in vivo, preclinical and clinical studies suggest that both aspects of glucocorticoid rhythmicity are preserved among mammalian species and are important for brain function. The central nervous system is exposed to both aspects of the hormonal rhythm and has developed mechanisms able to perceive them and translate them to differential cellular events, genomic and non-genomic. Thus, glucocorticoid rhythmicity regulates various physiological neural and glial processes, under baseline and stressful conditions, and hormonal dysrhythmicity has been associated with cognitive and behavioural defects. This raises a number of clinical implications concerning (i) glucocorticoid involvement in neuropsychiatric disease and (ii) improving the therapeutic efficacy or expanding the role of glucocorticoid-based treatments in such conditions.

Background: Meta-analysis and meta-synthesis have been developed to synthesize results across published studies; however, they are still largely grounded in what is already published, missing the tacit 'between the lines' knowledge generated during many research projects that are not intrinsic to the main objectives of studies., Objective: To develop a novel approach to expand and deepen meta-syntheses using researchers' experience, tacit knowledge and relevant unpublished materials., Methods: We established new collaborations among primary health care researchers from different contexts based on common interests in reforming primary care service delivery and a diversity of perspectives. Over 2 years, the team met face-to-face and via tele- and video-conferences to employ the Collaborative Reflexive Deliberative Approach (CRDA) to discuss and reflect on published and unpublished results from participants' studies to identify new patterns and insights., Results: CRDA focuses on uncovering critical insights, interpretations hidden within multiple research contexts. For the process to work, careful attention must be paid to ensure sufficient diversity among participants while also having people who are able to collaborate effectively. Ensuring there are enough studies for contextual variation also matters. It is necessary to balance rigorous facilitation techniques with the creation of safe space for diverse contributions., Conclusions: The CRDA requires large commitments of investigator time, the expense of convening facilitated retreats, considerable coordination, and strong leadership. The process creates an environment where interactions among diverse participants can illuminate hidden information within the contexts of studies, effectively enhancing theory development and generating new research questions and strategies.

Background: Most Western nations have sought primary care (PC) reform due to the rising costs of health care and the need to manage long-term health conditions. A common reform-the introduction of inter-professional teams into traditional PC settings-has been difficult to implement despite financial investment and enthusiasm., Objective: To synthesize findings across five jurisdictions in three countries to identify common contextual factors influencing the successful implementation of teamwork within PC practices., Methods: An international consortium of researchers met via teleconference and regular face-to-face meetings using a Collaborative Reflexive Deliberative Approach to re-analyse and synthesize their published and unpublished data and their own work experience. Studies were evaluated through reflection and facilitated discussion to identify factors associated with successful teamwork implementation. Matrices were used to summarize interpretations from the studies., Results: Seven common levers influence a jurisdiction's ability to implement PC teams. Team-based PC was promoted when funding extended beyond fee-for-service, where care delivery did not require direct physician involvement and where governance was inclusive of non-physician disciplines. Other external drivers included: the health professional organizations' attitude towards team-oriented PC, the degree of external accountability required of practices, and the extent of their links with the community and medical neighbourhood. Programs involving outreach facilitation, leadership training and financial support for team activities had some effect., Conclusion: The combination of physician dominance and physician aligned fee-for-service payment structures provide a profound barrier to implement team-oriented PC. Policy makers should carefully consider the influence of these and our other identified drivers when implementing team-oriented PC.

Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy., Competing Interests: The authors declare no conflict of interest.

Objectives: To review the accuracy of diagnoses of chronic obstructive pulmonary disease (COPD) in primary care in Australia, and to describe smokers' experiences with and preferences for smoking cessation., Design, Setting and Participants: Patients were invited to participate if they were at least 40 years old and had visited participating general practice clinics in Melbourne at least twice during the previous 12 months, reported being current or ex-smokers with a smoking history of at least 10 pack-years, or were being managed for COPD. Interviews based on a structured questionnaire and case finding (FEV1/FEV6 measurement) were followed, when appropriate, by spirometry testing and assessment of health-related quality of life, dyspnoea and symptoms., Results: 1050 patients attended baseline interviews (February 2015 - April 2017) at 41 practices. Of 245 participants managed for COPD, 130 (53.1%) met the spirometry-based definition (post-bronchodilator FEV1/FVC < 0.7) or had a clinical correlation; in 37% of cases COPD was not confirmed, and no definitive result was obtained for 9.8% of patients. Case finding and subsequent spirometry testing identified 142 new COPD cases (17.6% of participants without prior diagnosis; 95% CI, 15.1-20.5%). 690 participants (65.7%) were current smokers, of whom 360 had attempted quitting during the previous 12 months; 286 (81.0% of those attempting to quit) reported difficulties during previous quit attempts. Nicotine replacement therapy (205, 57.4%) and varenicline (110, 30.8%) were the most frequently employed pharmacological treatments; side effects were common. Hypnotherapy was the most popular non-pharmacological option (62 smokers, 17%); e-cigarettes were tried by 38 (11%). 187 current smokers (27.6%) would consider using e-cigarettes in future attempts to quit., Conclusions: COPD was both misdiagnosed and missed. Case finding and effective use of spirometry testing could improve diagnosis. Side effects of smoking cessation medications and difficulties during attempts to quit smoking are common. Health professionals should emphasise evidence-based treatments, and closely monitor quitting difficulties and side effects of cessation aids., Trial Registration: Australian New Zealand Clinical Trials Registry ACTRN12614001155684.

Glucocorticoids mediate plethora of actions throughout the human body. Within the brain, they modulate aspects of immune system and neuroinflammatory processes, interfere with cellular metabolism and viability, interact with systems of neurotransmission and regulate neural rhythms. The influence of glucocorticoids on memory and emotional behaviour is well known and there is increasing evidence for their involvement in many neuropsychiatric pathologies. These effects, which at times can be in opposing directions, depend not only on the concentration of glucocorticoids but also the duration of their presence, the temporal relationship between their fluctuations, the co-influence of other stimuli, and the overall state of brain activity. Moreover, they are region- and cell type-specific. The molecular basis of such diversity of effects lies on the orchestration of the spatiotemporal interplay between glucocorticoid- and mineralocorticoid receptors, and is achieved through complex dynamics, mainly mediated via the circadian and ultradian pattern of glucocorticoid secretion. More sophisticated methodologies are therefore required to better approach the study of these hormones and improve the effectiveness of glucocorticoid-based therapeutics., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Deviation from the physiological glucocorticoid dynamics (circadian and underlying ultradian rhythmicity) is a common characteristic of various neuropsychiatric and endocrine disorders as well as glucocorticoid-based therapeutics. These states may be accompanied by neuropsychiatric symptomatology, suggesting continuous dynamic glucocorticoid equilibrium is essential for brain homeostasis., Methods/design: The study consists of two parts. The preliminary stage of the study aims to validate (technically and pharmacologically) and optimise three different patterns of systemic cortisol administration in man. These patterns are based on the combinatory administration of metyrapone, to suppress endogenous cortisol production, and concurrent hydrocortisone replacement. The second, subsequent, core part of the study is a randomised, double-blinded, placebo-controlled, crossover study, where participants (healthy male individuals aged 18-60 years) will undergo all three hydrocortisone replacement schemes. During these infusion regimes, we plan a number of neurobehavioural tests and imaging of the brain to assess neural processing, emotional reactivity and perception, mood and self-perceived well-being. The psychological tests include: ecological momentary assessment, P1vital Oxford Emotional Test Battery and Emotional Potentiated Startle Test, Leeds Sleep Evaluation Questionnaire and the visual working memory task (n-back). The neuroimaging protocol combines magnetic resonance sequences that capture data related to the functional and perfusion status of the brain., Discussion: Results of this clinical trial are designed to evaluate the impact (with possible mechanistic insights) of different patterns of daily glucocorticoid dynamics on neural processing and reactivity related to emotional perception and mood. This evidence should contribute to the optimisation of the clinical application of glucocorticoid-based therapeutics., Trial Registration: UK Clinical Research Network, IRAS Ref: 106181, UKCRN-ID-15236 (23 October 2013).