Effects of interactions between anthropogenic stressors and recurring perturbations on ecosystem resilience and collapse.

Insights into declines in ecosystem resilience and their causes and effects can inform preemptive action to avoid ecosystem collapse and loss of biodiversity, ecosystem services, and human well-being. Empirical studies of ecosystem collapse are rare and hampered by ecosystem complexity, nonlinear and lagged responses, and interactions across scales. We investigated how an anthropogenic stressor could diminish ecosystem resilience to a recurring perturbation by altering a critical ecosystem driver. We studied groundwater-dependent, peat-accumulating, fire-prone wetlands known as upland swamps in southeastern Australia. We hypothesized that underground mining (stressor) reduces resilience of these wetlands to landscape fires (perturbation) by diminishing groundwater, a key ecosystem driver. We monitored soil moisture as an indicator of ecosystem resilience during and after underground mining. After landscape fire, we compared responses of multiple state variables representing ecosystem structure, composition, and function in swamps within the mining footprint with unmined reference swamps. Soil moisture declined without recovery in swamps with mine subsidence (i.e., undermined), but was maintained in reference swamps over 8 years (effect size 1.8). Relative to burned reference swamps, burned undermined swamps showed greater loss of peat via substrate combustion; reduced cover, height, and biomass of regenerating vegetation; reduced postfire plant species richness and abundance; altered plant species composition; increased mortality rates of woody plants; reduced postfire seedling recruitment; and extirpation of a hydrophilic animal. Undermined swamps therefore showed strong symptoms of postfire ecosystem collapse, whereas reference swamps regenerated vigorously. We found that an anthropogenic stressor diminished the resilience of an ecosystem to recurring perturbations, predisposing it to collapse. Avoidance of ecosystem collapse hinges on early diagnosis of mechanisms and preventative risk reduction. It may be possible to delay or ameliorate symptoms of collapse or to restore resilience, but the latter appears unlikely in our study system due to fundamental alteration of a critical ecosystem driver. Efectos de las interacciones entre los estresantes antropogénicos y las perturbaciones recurrentes sobre la resiliencia y el colapso de los ecosistemas.

La comprensión de la declinación en la resiliencia de los ecosistemas y sus causas y efectos puede orientar las acciones preventivas para evitar el colapso ecosistémico y la pérdida de biodiversidad, servicios ambientales y bienestar humano. Los estudios empíricos del colapso ecosistémico son escasos y se enfrentan a obstáculos como la complejidad del ecosistema, respuestas rezagadas y no lineales e interacciones entre las escalas. Investigamos cómo un estresante antropogénico podría reducir la resiliencia del ecosistema a una perturbación recurrente mediante la alteración de un causante importante. Estudiamos los humedales dependientes de aguas subterráneas que acumulan turbas y son propicios a incendios conocidos como pantanos de tierras altas en el sureste de Australia. Nuestra hipótesis fue que la minería subterránea (estresante) reduce la resiliencia de estos humedales a incendios (perturbación) al disminuir el agua subterránea, un causante clave para el ecosistema. Monitoreamos la humedad del suelo como un indicador de la resiliencia del ecosistema durante y después de la minería subterránea. Después de los incendios, comparamos la respuesta de múltiples variables de estado que representaban la estructura, composición y función del ecosistema en los pantanos dentro de la huella minera con los pantanos referenciales sin minería. La humedad del suelo declinó sin recuperación en los pantanos con hundimientos mineros (es decir, socavones) pero se mantuvo en los pantanos referenciales durante ocho años (tamaño del efecto: 1.8). En relación a los pantanos referenciales incendiados, los pantanos con socavones e incendios mostraron una mayor pérdida de turba mediante la combustión del sustrato; reducción en la cobertura, altura y regeneración de biomasa de la vegetación; reducción en la riqueza y abundancia de especies vegetales post incendio; alteraciones en la composición de especies vegetales; incremento en la mortalidad de las plantas leñosas; reducción en el reclutamiento post incendio de plántulas; y la extirpación de un animal hidrofílico. Por lo tanto, los pantanos con socavones mostraron síntomas fuertes de un colapso ecosistémico post incendio, mientras que los pantanos referenciales se regeneraron vigorosamente. Descubrimos que los estresantes antropogénicos redujeron la resiliencia de un ecosistema a perturbaciones recurrentes, lo que lo predispone al colapso. La eliminación de este colapso depende de un diagnóstico temprano de mecanismos y reducción del riesgo preventivo. Puede ser posible retardar o mitigar los síntomas del colapso o restaurar la resiliencia, aunque lo último parece ser improbable en nuestro sistema de estudio debido a la alteración fundamental de un causante importante del ecosistema.

A Model Predicting Healthcare Capacity Gaps For Alzheimer's Disease-Modifying Treatment in Canada.

BACKGROUND: Alzheimer's disease (AD) is experienced by > 600,000 Canadians. Disease-modifying therapies (DMTs) for earlier stages of disease are in development. Existing health system capacity constraints and the need for biomarker-driven diagnostics to confirm DMT eligibility are concerning. This study aimed to characterize the capacity gap related to early AD (eAD) treatment with DMTs in Canada. METHODS: A capacity model was developed to simulate the flow of a patient from screening to treatment for eAD to quantify the gap between available and required healthcare resources and qualify the bottlenecks restricting the patient journey at a provincial and national level. The model inputs (epidemiological, human resource, and clinical) were evidence-based, healthcare professional-, and patient advocate-informed. RESULTS: The model estimated that nationally < 2% of patients would have access to the required healthcare resources for treatment with a DMT. Eligibility assessment represented the step with the largest capacity gap across all provinces, with a wait list of about 382,000 Canadians one year following DMT introduction. The top three resource gaps included AD specialist time and positron emission tomography and magnetic resonance imaging exam slots. Sensitivity analysis showed that full reliance on cerebrospinal fluid for eligibility testing increased capacity for assessment by about 47,000 patients. CONCLUSION: This model highlights that the Canadian health system is critically under-resourced to diagnose, assess, and treat patients with eAD with DMT. It underscores an urgent need for national policy and provincial resource allocation to close the gap.

A century past the discovery of insulin: global progress and challenges for type 1 diabetes among children and adolescents in low-income and middle-income countries.

Type 1 diabetes is on the rise globally; however, the burden of mortality remains disproportionate in low-income and middle-income countries (LMICs). As 2021 marks 100 years since the discovery of insulin, we revisit progress, global burden of type 1 diabetes trends, and understanding of the pathogenesis and management practices related to the disease. Despite much progress, inequities in access and availability of insulin formulations persist and are reflected in differences in survival and morbidity patterns related to the disease. Some of these inequities have also been exacerbated by health-system challenges during the COVID-19 pandemic. There is a clear opportunity to improve access to insulin and related essential technologies for improved management of type 1 diabetes in LMICs, especially as a part of universal health coverage. These improvements will require concerted action and investments in human resources, community engagement, and education for the timely diagnosis and management of type 1 diabetes, as well as adequate health-care financing. Further research in LMICs, especially those in Africa, is needed to improve our understanding of the burden, risk factors, and implementation strategies for managing type 1 diabetes.

Clinical and biomechanical factors associated with falls and rheumatoid arthritis: baseline cohort with longitudinal nested case-control study.

OBJECTIVE: To identify the clinical and biomechanical characteristics associated with falls in people with RA. METHODS: A total of 436 people ≥60 years of age with RA completed a 1 year prospective survey of falls in the UK. At baseline, questionnaires recorded data including personal and medical history, pain and fatigue scores, health-related quality of life (HRQoL), physical activity and medication history. The occurrence of falls wasmonitored prospectively over 12 months by monthly self-reporting. A nested sample of 30 fallers (defined as the report of one or more falls in 12 months) and 30 non-fallers was evaluated to assess joint range of motion (ROM), muscle strength and gait parameters. Multivariate regression analyses were undertaken to determine variables associated with falling. RESULTS: Compared with non-fallers (n = 236), fallers (n = 200) were older (P = 0.05), less likely to be married (P = 0.03), had higher pain scores (P < 0.01), experienced more frequent dizziness (P < 0.01), were frequently taking psychotropic medications (P = 0.02) and reported lower HRQoL (P = 0.02). Among those who underwent gait laboratory assessments, compared with non-fallers, fallers showed a greater anteroposterior (AP; P = 0.03) and medial-lateral (ML) sway range (P = 0.02) and reduced isokinetic peak torque and isometric strength at 60° knee flexion (P = 0.03). Fallers also showed shorter stride length (P = 0.04), shorter double support time (P = 0.04) and reduced percentage time in swing phase (P = 0.02) and in knee range of motion through the gait cycle (P < 0.01). CONCLUSION: People with RA have distinct clinical and biomechanical characteristics that place them at increased risk of falling. Assessment for these factors may be important to offer more targeted rehabilitation interventions.

Awakening Canadians to ageism: a study protocol.

BACKGROUND: Making fun of growing older is considered socially acceptable, yet ageist humour reinforces negative stereotypes that growing old is linked with physical and mental deterioration, dependence, and less social value. Such stereotypes and discrimination affect the wellbeing of older people, the largest demographic of Canadians. While ageism extends throughout professions and social institutions, we expect nurses-the largest and most trusted group of healthcare professionals-to provide non-ageist care to older people. Unfortunately, nurses working with older people often embrace ageist beliefs and nursing education programs do not address sufficient anti-ageism content despite gerontological nursing standards and competencies. METHODS: To raise awareness of ageism in Canada, this quasi-experimental study will be supported by partnerships between older Canadians, advocacy organizations, and academic gerontological experts which will serve as an advisory group. The study, guided by social learning theory, will unfold in two parts. In Phase 1, we will use student nurses as a test case to determine if negative stereotypes and ageist perceptions can be addressed through three innovative e-learning activities. The activities employ gamification, videos, and simulations to: (1) provide accurate general information about older people, (2) model management of responsive behaviours in older people with cognitive impairment, and (3) dispel negative stereotypes about older people as dependent and incontinent. In Phase 2, the test case findings will be shared with the advisory group to develop a range of knowledge mobilization strategies to dispel ageism among healthcare professionals and the public. We will implement key short term strategies. DISCUSSION: Findings will generate knowledge on the effectiveness of the e-learning activities in improving student nurses' perceptions about older people. The e-learning learning activities will help student nurses acquire much-needed gerontological knowledge and skills. The strength of this project is in its plan to engage a wide array of stakeholders who will mobilize the phase I findings and advocate for positive perspectives and accurate knowledge about aging-older Canadians, partner organizations (Canadian Gerontological Nurses Association, CanAge, AgeWell), and gerontological experts.

ERAP1 association with ankylosing spondylitis is attributable to common genotypes rather than rare haplotype combinations.

We investigated the proposal that ankylosing spondylitis (AS) is associated with unusual ERAP1 genotypes. ERAP1 haplotypes were constructed for 213 AS cases and 46 rheumatoid arthritis controls using family data. Haplotypes were generated from five common ERAP1 single nucleotide polymorphisms (SNPs)-rs2287987 (M349V), rs30187 (K528R), rs10050860 (D575N), rs17482078 (R725Q), and rs27044 (Q730E). Haplotype frequencies were compared using Fisher's exact test. ERAP1 haplotypes imputed from the International Genetics of AS Consortium (IGAS) Immunochip study were also studied. In the family study, we identified only four common ERAP1 haplotypes ("VRNQE," "MKDRQ," "MRDRE," and "MKDRE") in both AS cases and controls apart from two rare (<0.5%) previously unreported haplotypes. There were no examples of the unusual ERAP1 haplotype combination ("*001/*005") previously reported by others in 53% of AS cases. As expected, K528-bearing haplotypes were increased in the AS family study (AS 43% vs. control 35%), due particularly to an increase in the MKDRQ haplotype (AS 35% vs. control 25%, P = 0.01). This trend was replicated in the imputed Immunochip data for the two K528-bearing haplotypes MKDRQ (AS 33% vs. controls 27%, P = 1.2 × 10-24) and MKDRE (AS 8% vs. controls 7%, P = 0.004). The ERAP1 association with AS is therefore predominantly attributable to common ERAP1 haplotypes and haplotype combinations.

The severity of ankylosing spondylitis and responses to anti-tumour necrosis factor biologics are not influenced by the tumour necrosis factor receptor polymorphism incriminated in multiple sclerosis.

Genetic polymorphism (rs1800693) of TNFRSF1A (type 1 tumour necrosis factor receptor) encodes a potentially anti-inflammatory soluble truncated form of the p55 receptor, which is associated with predisposition to multiple sclerosis but protection against ankylosing spondylitis (AS). We analysed 2917 UK Caucasian cases by linear and logistic regression for associations of rs1800693 with disease severity assessed by the Bath Ankylosing Spondylitis measures of disease activity and function (BASDAI, BAS-G and BASFI) and/or responses to anti-TNF therapy. In contrast to predictions, rs1800693 GG homozygotes actually had significantly worse BASDAI (mean 4.2, 95% CI: 4-4.5) than AA homozygotes (mean 3.8, 95% CI: 3.7-4) in both the unadjusted (difference = 0.4, p = 0.006) and adjusted analyses (difference = 0.2-0.5, p = 0.002-0.04 depending on the adjustment model). We found no evidence that rs1900693 predicted functional status (BASFI) or global disease scores (BAS-G), and it exerted no influence on either the intention to treat with or efficacy of anti-TNF treatment.

Patient experiences of participation in a medical student teaching workshop.

OBJECTIVES: To investigate the motivations for and experiences of patients who actively participate in a workshop to teach medical students about chronic disease. DESIGN: Descriptive study using structured telephone or e-mail-based questionnaire exploring the views of 'patient tutors' who participate in a 'living with chronic disease' workshop. PARTICIPANTS: 'Patient tutors' with a chronic medical condition who had participated in at least one 'living with chronic disease' workshop for medical students at Oxford University Medical School. RESULTS: Patient motivating factors can be divided into two groups, direct benefits such as companionship or improved knowledge of their condition, and a teaching role involving an altruistic desire to give something back, and wanting to educate the doctors of the future. Importantly, most patients participated multiple times over a number of years despite no remuneration for their time other than expenses. CONCLUSIONS: Patients appear highly motivated to educate medical students about chronic disease, due to a combination of personal benefits and an altruistic desire to 'give something back'. This suggests that they present an invaluable and currently undermobilized resource for the future of medical education.

Developing a Research Agenda on Resident-to-Resident Aggression: Recommendations From a Consensus Conference.

This article provides an overview of the development of a research agenda on resident-to-resident aggression (RRA) in long-term care facilities by an expert panel of researchers and practitioners. A 1-day consensus-building workshop using a modified Delphi approach was held to gain consensus on nomenclature and an operational definition for RRA, to identify RRA research priorities, and to develop a roadmap for future research on these priorities. Among the six identified terms in the literature, RRA was selected. The top five priorities were: (a) developing/assessing RRA environmental interventions; (b) identification of the environmental factors triggering RRA; (c) incidence/prevalence of RRA; (d) developing/assessing staff RRA education interventions; and (e) identification of RRA perpetrator and victim characteristics. Given the significant harm RRA poses for long-term care residents, this meeting is an important milestone, as it is the first organized effort to mobilize knowledge on this under-studied topic at the research, clinical, and policy levels.

Inhibition of the thioesterase activity of human fatty acid synthase by 1,4- and 9,10-diones.

Fatty acid synthase (FASN) is the enzyme that synthesizes fatty acids de novo in human cells. Although FASN is generally expressed at low levels in most normal tissues, its expression is highly upregulated in many cancers. Consistent with this notion, inhibition of FASN activity has demonstrated potential to halt proliferation and induce cell death in vitro and to block tumor growth in vivo. Consequently, FASN is widely recognized as a valuable therapeutic target. In this report, we describe a variety of 1,4-quinones and 9,10-anthraquinones, including several natural compounds and some newly synthesized compounds, that potently inhibit the thioesterase (TE) domain of FASN. Inhibition of recombinant TE activity, inhibition of cellular FASN, and cytotoxicity in human prostate cancer cell lines and normal fibroblasts, is shown for the most potent inhibitors. Collectively, the data illustrate the novel inhibitory capacity of the 1,4-quinone and 9,10-anthraquinone pharmacophores against FASN.

Young Adults' Hopes Regarding Noncommunicable Disease (NCD) Prevention and Management After the SARS-CoV-2 Virus Pandemic: Reflections From the NCD Child #YouthCOVIDCHAT Campaign.

PURPOSE: The SARS-CoV-2 virus pandemic has left a massive global death toll in its wake. Associated restrictions, precautions and lockdowns have disrupted daily routines, which has been associated with social isolation and major health implications for the world's youth. This paper shares young adults' visions for life beyond the pandemic as it relates to the prevention and management of noncommunicable diseases (NCDs). METHODS: NCD Child hosted a global Twitter campaign for young adults, some of whom are living with NCDs, to express their reflections on life beyond the pandemic. Contributions were subjected to qualitative thematic analysis. RESULTS: 52 responses from the campaign described six main themes: Health system strengthening; Access to care; Issues of sustainability, including the environment and the economy; Human rights, equity, and social issues; Mental health, and NCD prevention. DISCUSSION: Young adults expressed optimism about postpandemic life and emphasized the importance of comprehensive intersectoral approaches to create resilient health systems.

The phenotype of MEGF8-related Carpenter syndrome (CRPT2) is refined through the identification of eight new patients.

Carpenter syndrome (CRPTS) is a rare autosomal recessive condition caused by biallelic variants in genes that encode negative regulators of hedgehog signalling (RAB23 [CRPT1] or, more rarely, MEGF8 [CRPT2]), and is characterised by craniosynostosis, polysyndactyly, and other congenital abnormalities. We describe a further six families comprising eight individuals with MEGF8-associated CRPT2, increasing the total number of reported cases to fifteen, and refine the phenotype of CRPT2 compared to CRPT1. The core features of craniosynostosis, polysyndactyly and (in males) cryptorchidism are almost universal in both CRPT1 and CRPT2. However, laterality defects are present in nearly half of those with MEGF8-associated CRPT2, but are rare in RAB23-associated CRPT1. Craniosynostosis in CRPT2 commonly involves a single midline suture in comparison to the multi-suture craniosynostosis characteristic of CRPT1. No patient to date has carried two MEGF8 gene alterations that are both predicted to lead to complete loss-of-function, suggesting that a variable degree of residual MEGF8 activity may be essential for viability and potentially contributing to variable phenotypic severity. These data refine the phenotypic spectrum of CRPT2 in comparison to CRPT1 and more than double the number of likely pathogenic MEGF8 variants in this rare disorder.

Consent and Inclusion of People Living with Dementia (PLWD) in Research: Establishing a Canadian Agenda for Inclusive Rights-Based Practices.

BACKGROUND: People living with dementia (PLWD) may want to participate in research, but the guidelines and processes enacted across various contexts may prohibit this from happening. OBJECTIVE: Understanding the experiences of people with lived experiences of dementia requires meaningful inclusion in research, as is consistent with rights-based perspectives. Currently, the inclusion of PLWD in Canadian research is complex, and guidelines and conceptual frameworks have not been fully developed. METHODS: This research note outlines a three-year proof-of-concept grant on the inclusion and consent of PLWD in research. FINDINGS: It presents a brief report on some of the contradictions and challenges that exist in legislation, research guidelines, and research practices and raises a series of questions as part of an agenda on rights and inclusion of PLWD in research. DISCUSSION: It suggests conceptual, legal, and policy issues that need to be addressed and invites Canadian researchers to re-envision research practices and to advocate for law and policy reform that enables dementia research to align and respect the rights and personhood of PLWD.

An evidence gap map of interventions for noncommunicable diseases and risk factors among children and adolescents.

Substance misuse, obesity, mental health conditions, type 1 diabetes, cancers, and cardiovascular and chronic respiratory diseases together account for 41% of disability-adjusted life years linked to noncommunicable diseases (NCDs) among children and adolescents worldwide. However, the evidence on risk factors and interventions for this age group is scarce. Here we searched four databases to generate an evidence gap map of existing interventions and research gaps for these risk factors and NCDs. We mapped 159 reviews with 2,611 primary studies; most (96.2%) were conducted in high-income countries, and only 100 studies (3.8%) were from low- and middle-income countries (LMICs). The efficacy of therapeutic interventions on biomarkers and adverse events for NCDs appears to be well evidenced. Interventions for mental health conditions appear to be moderately evidenced, while interventions for obesity and substance misuse appear to be moderate to very low evidenced. Priority areas for future research include evaluating digital health platforms to support primary NCD prevention and management, and evaluating the impact of policy changes on the prevalence of obesity and substance misuse. Our findings highlight the wide disparity of evidence between high-income countries and LMICs. There is an urgent need for increased, targeted financing to address the research gaps in LMICs.

The CD3 zeta subunit contains a phosphoinositide-binding motif that is required for the stable accumulation of TCR-CD3 complex at the immunological synapse.

T cell activation involves a cascade of TCR-mediated signals that are regulated by three distinct intracellular signaling motifs located within the cytoplasmic tails of the CD3 chains. Whereas all the CD3 subunits possess at least one ITAM, the CD3 ε subunit also contains a proline-rich sequence and a basic-rich stretch (BRS). The CD3 ε BRS complexes selected phosphoinositides, interactions that are required for normal cell surface expression of the TCR. The cytoplasmic domain of CD3 ζ also contains several clusters of arginine and lysine residues. In this study, we report that these basic amino acids enable CD3 ζ to complex the phosphoinositides PtdIns(3)P, PtdIns(4)P, PtdIns(5)P, PtdIns(3,5)P(2), and PtdIns(3,4,5)P(3) with high affinity. Early TCR signaling pathways were unaffected by the targeted loss of the phosphoinositide-binding functions of CD3 ζ. Instead, the elimination of the phosphoinositide-binding function of CD3 ζ significantly impaired the ability of this invariant chain to accumulate stably at the immunological synapse during T cell-APC interactions. Without its phosphoinositide-binding functions, CD3 ζ was concentrated in intracellular structures after T cell activation. Such findings demonstrate a novel functional role for CD3 ζ BRS-phosphoinositide interactions in supporting T cell activation.

Now I know what I don't know: how to reform the foundation years to fit 21st-century medicine.

The two-year Foundation Programme was introduced in the UK as a structured way to deal with the lack of training, support and difficulties with career progression associated with the old senior house office (SHO) grade. Although it provides a clear curriculum and structure for career progression, there is growing dissatisfaction among participants about the difference between the aspirations of the Foundation Programme and the realities of working as a foundation doctor. In particular, the erosion of the traditional team structure, difficulties with the system of assessment and a feeling that the career structure is now too rigid has led to a situation where doctors are being forced to choose their specialty training too early and often with little experience in the specialty. To what extent is the Foundation Programme fit for purpose? This will be considered together with suggestions for future reform.

English care home staff morale and preparedness during the COVID pandemic: A longitudinal analysis.

BACKGROUND: Staff actions to prevent infection introduction and transmission in long-term care facilities (LTCFs) were key to reducing morbidity and mortality from COVID-19. Implementing infection control measures (ICMs) requires training, adherence and complex decision making while trying to deliver high quality care. We surveyed LTCF staff in England about their preparedness and morale at 3 timepoints during the COVID-19 epidemic. METHODS: Online structured survey targeted at LTCF workers (any role) administered at 3 timepoints (November 2020-January 2021; August-November 2021; March-May 2022). Narrative summary of answers, narrative and statistical summary (proportionality with Pearson's chi-square or Fisher's Exact Test) of possible differences in answers between waves. RESULTS: Across all 3 survey waves, 387 responses were received. Morale, attitudes towards working environment and perception about colleague collaboration were mostly positive at all survey points. Infection control training was perceived as adequate. Staff felt mostly positive emotions at work. The working environment remained challenging. Masks were the single form of PPE most consistently used; eye protection the least used. Mask-wearing was linked to poorer communication and resident discomfort as well as mild negative health impacts on many staff, such as dehydration and adverse skin reactions. Hand sanitizer caused skin irritation. CONCUSIONS: Staff morale and working practices were generally good even though the working environment provided many new challenges that did not exist pre-pandemic.

Outcomes in Ankle Replacement Study (OARS).

Aims: The aim of this study was to capture 12-month outcomes from a representative multicentre cohort of patients undergoing total ankle arthroplasty (TAA), describe the pattern of patient-reported outcome measures (PROMs) at 12 months, and identify predictors of these outcome measures. Methods: Patients listed for a primary TAA at 19 NHS hospitals between February 2016 and October 2017 were eligible. PROMs data were collected preoperatively and at six and 12 months including: Manchester-Oxford Foot and Ankle Questionnaire (MOXFQ (foot and ankle)) and the EuroQol five-dimension five-level questionnaire (EQ-5D-5L). Radiological pre- and postoperative data included Kellgren-Lawrence score and implant position measurement. This was supplemented by data from the National Joint Registry through record linkage to determine: American Society of Anesthesiologists (ASA) grade at index procedure; indication for surgery, index ankle previous fracture; tibial hind foot alignment; additional surgery at the time of TAA; and implant type. Multivariate regression models assessed outcomes, and the relationship between MOXFQ and EQ-5D-5L outcomes, with patient characteristics. Results: Data from 238 patients were analyzed. There were significant improvements in MOXFQ and EQ-5D-5L among people who underwent TAA at six- and 12-month assessments compared with preoperative scores (p < 0.001). Most improvement occurred between preoperative and six months, with little further improvement at 12 months. A greater improvement in MOXFQ outcome postoperatively was associated with older age and more advanced radiological signs of ankle osteoarthritis at baseline. Conclusion: TAA significantly benefits patients with end-stage ankle disease. The lack of substantial further overall change between six and 12 months suggests that capturing PROMs at six months is sufficient to assess the success of the procedure. Older patients and those with advanced radiological disease had the greater gains. These outcome predictors can be used to counsel younger patients and those with earlier ankle disease on the expectations of TAA.

Why the trial researcher matters: Day-to-day work viewed through the lens of normalization process theory.

Researchers working in the field, the places where research-relevant activity happens, are essential to recruitment and data collection in randomised controlled trials (RCTs). This study aimed to understand the nature of this often invisible work. Data were generated through an RCT of a pharmacist-led medication management service for older people in care homes. The study was conducted over three years and employed seven Research Associates (RA) working in Scotland, Northern Ireland, and England. Weekly research team meetings and Programme Management Group meetings naturally generated 129 sets of minutes. This documentary data was supplemented with two end-of-study RA debriefing meetings. Data were coded to sort the work being done in the field, then deductively explored through the lens of Normalization Process Theory to enable a greater understanding of the depth, breadth and complexity of work carried out by these trial delivery RAs. Results indicate RAs helped stakeholders and participants make sense of the research, they built relationships with participants to support retention, operationalised complex data collection procedures and reflected on their own work contexts to reach agreement on changes to trial procedures. The debrief discussions enabled RAs to explore and reflect on experiences from the field which had affected their day-to-day work. The learning from the challenges faced in facilitating care home research may be useful to inform future research team preparation for complex interventions. Scrutinising these data sources through the lens of NPT enabled us to identify RAs as linchpins in the successful conduct of a complex RCT study.

Availability and access to pediatric diabetes care: a global descriptive study.

A decade since the discovery of insulin, the increasing prevalence of type 1 diabetes mellitus (T1DM) has underscored the prevailing inequalities in the provision of essential care for T1DM worldwide. However, the details on the availability of insulin types and associated medical devices remain unclear. A cross-sectional electronic survey was distributed across a global network of pediatric societies under the umbrella of the International Pediatric Association (IPA). Access to and availability of pediatric diabetes care were investigated using standardized questions. Responses from 25 of 132 pediatric societies across six regions were included. Pediatric endocrinologists typically manage T1DM together with pediatricians or adult endocrinologists. Nonetheless, 24% of the respondents reported pediatricians to be the sole healthcare professionals. According to the respondents, the patients were either partially or completely responsible for payments of insulin (40%), A1C (24%), C-peptide (28%), and antibody testing for diagnosis (28%). Government support is generally available for insulin, but this was merely 20% for insulin pumps and 12% for continuous glucose monitors. There are considerable disparities in the access, availability, and affordability of diabetes testing, medications, and support between countries with significant out-of-pocket payments for care. Country- and region-specific improvements to national programs are necessary to achieve optimal pediatric diabetes care globally.