Competition between cross-linking and force-induced local conformational changes determines the structure and mechanics of labile protein networks.

Folded protein hydrogels are emerging as promising new materials for medicine and healthcare applications. Folded globular proteins can be modelled as colloids which exhibit site specific cross-linking for controlled network formation. However, folded proteins have inherent mechanical stability and unfolded in response to an applied force. It is not yet understood how colloidal network theory maps onto folded protein hydrogels and whether it models the impact of protein unfolding on network properties. To address this, we study a hybrid system which contains folded proteins (patchy colloids) and unfolded proteins (biopolymers). We use a model protein, bovine serum albumin (BSA), to explore network architecture and mechanics in folded protein hydrogels. We alter both the photo-chemical cross-linking reaction rate and the mechanical properties of the protein building block, via illumination intensity and redox removal of robust intra-protein covalent bonds, respectively. This dual approach, in conjunction with rheological and structural techniques, allows us to show that while reaction rate can 'fine-tune' the mechanical and structural properties of protein hydrogels, it is the force-lability of the protein which has the greatest impact on network architecture and rigidity. To understand these results, we consider a colloidal model which successfully describes the behaviour of the folded protein hydrogels but cannot account for the behaviour observed in force-labile hydrogels containing unfolded protein. Alternative models are needed which combine the properties of colloids (folded proteins) and biopolymers (unfolded proteins) in cross-linked networks. This work provides important insights into the accessible design space of folded protein hydrogels without the need for complex and costly protein engineering, aiding the development of protein-based biomaterials.

Twelve tips for creating a works in progress conference that builds capacity for educational scholarship and creates a scholarly community.

Educators have implemented various strategies to build capacity for education scholarship, and often, these strategies focus on a specific set of interested individuals. We perceived a need for a strategy to engage a health professions education community with peer support. The purpose of these 12 tips is to describe an approach in place for nearly two decades that concurrently advances education scholarship and fosters a community that welcomes novices to experts. The approach is based on principles that not only build capacity and community but also stress the importance of alignment with the institution's missions. The tips guide setting up, conducting, and sustaining such an approach.

How Might we Build an Equitable Future? Design Justice, a Counternarrative to Dominant Approaches in Medical Education.

PHENOMENON: Marginalized individuals in medicine face many structural inequities which can have enduring consequences on their progress. Therefore, inequity must be addressed by dismantling underlying unjust policies, environments, and curricula. However, once these injustices have been taken apart, how do we build more just systems from the rubble? Many current strategies to address this question have foundational values of urgency, solutionism, and top-down leadership. APPROACH: This paper explores a counternarrative: Design Justice. As a set of guiding principles, Design Justice centers the experiences and perspectives of marginalized individuals and communities. These principles include mutual accountability and transparency, co-ownership, and community-led outcomes, and honoring local, traditional, Indigenous knowledge. FINDINGS: Rooted in critical scholarship and critical design, Design Justice recognizes the interconnectedness of various forms of marginalization and works to critically examine power dynamics that exist in every design process. These co-created principles act as practical guardrails, directing progress toward justice. INSIGHTS: This paper begins with an overview of Design Justice's history in critical scholarship and critical design, providing foundational background knowledge for medical educators, scholars, and leaders in key concepts of justice and design. We explore how the Design Justice principles were developed and have been applied across sectors, highlighting its applications, including education applications. Finally, we raise critical questions about medical education prompted by Design Justice.

HIT4HYPOS Continuous Glucose Monitoring Data Analysis: The Effects of High-Intensity Interval Training on Hypoglycemia in People With Type 1 Diabetes and Impaired Awareness of Hypoglycemia.

AIMS: To assess the impact of high-intensity interval training (HIIT) on hypoglycemia frequency and duration in people with type 1 diabetes (T1D) with impaired awareness of hypoglycemia (IAH). METHODS: Post hoc analysis of four weeks of continuous glucose monitoring (CGM) data from HIT4HYPOS; a parallel-group study comparing HIIT + CGM versus no exercise + CGM in 18 participants with T1D and IAH. RESULTS: When compared with those participating individuals not exercising, HIIT did not increase total hypoglycemia frequency, THypo(L1) 1.44 [1.00-2.77]% versus 2.53 [1.46-4.23]%; P = .335, THypo(L2) 0.25 [0.09-0.37]% versus 0.45 [0.20-0.78]%; P = .146, HIIT + CGM versus CGM, respectively, rate (EventPerWeekHypo 5.30 [3.35-8.27] #/week vs 7.45 [3.54-10.81] #/week, P = .340) or duration (DurationHypo 33.33 [27.60-39.10] minutes vs 39.56 [31.00-48.38] minutes; P = .219, HIIT + CGM vs CGM, respectively). There was a reduction in nocturnal hypoglycemia in those who carried out HIIT, THypo(L1) 0.50 [0.13-0.97]% versus 2.45 [0.77-4.74]%; P = .076; THypo(L2) 0.00 [0.00-0.03]% versus 0.49 [0.13-0.74]%; P = .006, HIIT + CGM versus CGM, respectively. CONCLUSIONS/INTERPRETATION: Based on CGM data collected from a real-world study of four weeks of HIIT versus no exercise in individuals with T1D and IAH, we conclude that HIIT does not increase hypoglycemia, and in fact reduces exposure to nocturnal hypoglycemia.

Clarifying and expanding equity in assessment by considering three orientations: Fairness, inclusion and justice.

CONTEXT: Despite increasing discussion and scholarship, equity in assessment is rarely defined and distinguished in a way that allows for shared understanding in medical education. This paper seeks to clarify and expand the conversation about equity in assessment by critically reviewing three distinct and evolving orientations toward equity in assessment. Orientations refers to the positions, attitudes, interests or priorities individuals can hold toward equity in assessment. The three orientations include fairness-oriented assessment, assessment for inclusion and justice-oriented assessment. While fairness-oriented assessment is a prevailing orientation in medical education, assessment for inclusion and justice-oriented assessment, originally developed in other fields of education, deserve careful consideration. METHODS: In this paper, the authors explore unique underpinning assumptions of each orientation by critically examining the foundational literature of each orientation. They reflect on the unique perspectives each orientation provides, including the actions one might take and what advantages and disadvantages might result from looking at equity in assessment from any one orientation. CONCLUSIONS: Informed by this reflection, the authors propose that to more effectively advance equity in assessment in medical education, those working in the field should clearly identify their respective orientations, intentionally choose methods, tools and measures aligned with their orientations and expand their work by exploring alternative orientations.

Elevations in plasma glucagon are associated with reduced insulin clearance after ingestion of a mixed-macronutrient meal in people with and without type 2 diabetes.

AIMS/HYPOTHESIS: The temporal suppression of insulin clearance after glucose ingestion is a key determinant of glucose tolerance for people without type 2 diabetes. Whether similar adaptations are observed after the ingestion of a mixed-macronutrient meal is unclear. METHODS: In a secondary analysis of data derived from two randomised, controlled trials, we studied the temporal responses of insulin clearance after the ingestion of a standardised breakfast meal consisting of cereal and milk in lean normoglycaemic individuals (n=12; Lean-NGT), normoglycaemic individuals with central obesity (n=11; Obese-NGT) and in people with type 2 diabetes (n=19). Pre-hepatic insulin secretion rates were determined by the deconvolution of C-peptide, and insulin clearance was calculated using a single-pool model. Insulin sensitivity was measured by an oral minimal model. RESULTS: There were divergent time course changes in insulin clearance between groups. In the Lean-NGT group, there was an immediate post-meal increase in insulin clearance compared with pre-meal values (p<0.05), whereas insulin clearance remained stable at baseline values in Obese-NGT or declined slightly in the type 2 diabetes group (p<0.05). The mean AUC for insulin clearance during the test was ~40% lower in the Obese-NGT (1.3 ± 0.4 l min-1 m-2) and type 2 diabetes (1.4 ± 0.7 l min-1 m-2) groups compared with Lean-NGT (1.9 ± 0.5 l min-1 m-2; p<0.01), with no difference between the Obese-NGT and type 2 diabetes groups. HOMA-IR and glucagon AUC emerged as predictors of insulin clearance AUC, independent of BMI, age or insulin sensitivity (adjusted R2=0.670). Individuals with increased glucagon AUC had a 40% reduction in insulin clearance AUC (~ -0.75 l min-1 m-2; p<0.001). CONCLUSIONS/INTERPRETATION: The ingestion of a mixed-macronutrient meal augments differing temporal profiles in insulin clearance among individuals without type 2 diabetes, which is associated with HOMA-IR and the secretion of glucagon. Further research investigating the role of hepatic glucagon signalling in postprandial insulin kinetics is warranted. TRIAL REGISTRATION: ISRCTN17563146 and ISRCTN95281775.

Differential COVID-19 case ascertainment by age and vaccination status in Victoria, Australia: a serosurveillance and record linkage study.

Objectives: To compare serological evidence of prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with linked coronavirus disease 2019 (COVID-19) case notification data in Victoria, Australia, and to determine in vitro SARS-CoV-2 neutralisation activity based on prior infection and vaccination history. Design, setting, participants: Four cross-sectional serological surveys were conducted between 30 June and 31 October 2022 (a period of Omicron BA.4/BA.5 dominance) using 1,974 residual serum samples obtained from the Victorian Infectious Diseases Reference Laboratory. Serological results were linked to COVID-19 case notification and vaccination data. Surrogate virus neutralisation testing was performed to obtain in vitro inhibition estimates by anti-nucleocapsid serostatus and COVID-19 vaccination history. Main outcome measures: Adjusted anti-SARS-CoV-2 spike and nucleocapsid seropositivity by sex, age and region of residence; adjusted proportion of cases notified by anti-nucleocapsid serostatus, age and number of COVID-19 vaccination doses received; adjusted percentage in vitro inhibition against wildtype and Omicron BA.4/BA.5 SARS-CoV-2 variants by anti-nucleocapsid serostatus and COVID-19 vaccination history. Results: The prevalence of anti-SARS-CoV-2 nucleocapsid antibodies was inversely proportional to age. In October 2022, prevalence was 84% (95% confidence interval [95% CI]: 75-93%) among 18-29-year-olds, compared to 39% (95% CI: 27-52%) among ≥ 80-year-olds. In most age groups, approximately 40% of COVID-19 cases appear to have been notified via existing surveillance mechanisms. Case notification was highest among individuals older than 80 years and people who had received COVID-19 vaccine booster doses. In vitro neutralisation of Omicron BA.4/BA.5 sub-variants was highest for individuals with evidence of both prior infection and booster vaccination. Conclusions: Under-notification of SARS-CoV-2 infections in the Victorian population is not uniform across age and vaccination strata. Seroprevalence data that give insights into case notification behaviour provide additional context for the interpretation of existing COVID-19 surveillance information.

COVID-19 outbreaks in residential aged care facilities: an agent-based modeling study.

Introduction: A disproportionate number of COVID-19 deaths occur in Residential Aged Care Facilities (RACFs), where better evidence is needed to target COVID-19 interventions to prevent mortality. This study used an agent-based model to assess the role of community prevalence, vaccination strategies, and non-pharmaceutical interventions (NPIs) on COVID-19 outcomes in RACFs in Victoria, Australia. Methods: The model simulated outbreaks in RACFs over time, and was calibrated to distributions for outbreak size, outbreak duration, and case fatality rate in Victorian RACFs over 2022. The number of incursions to RACFs per day were estimated to fit total deaths and diagnoses over time and community prevalence.Total infections, diagnoses, and deaths in RACFs were estimated over July 2023-June 2024 under scenarios of different: community epidemic wave assumptions (magnitude and frequency); RACF vaccination strategies (6-monthly, 12-monthly, no further vaccines); additional non-pharmaceutical interventions (10, 25, 50% efficacy); and reduction in incursions (30% or 60%). Results: Total RACF outcomes were proportional to cumulative community infections and incursion rates, suggesting potential for strategic visitation/staff policies or community-based interventions to reduce deaths. Recency of vaccination when epidemic waves occurred was critical; compared with 6-monthly boosters, 12-monthly boosters had approximately 1.2 times more deaths and no further boosters had approximately 1.6 times more deaths over July 2023-June 2024. Additional NPIs, even with only 10-25% efficacy, could lead to a 13-31% reduction in deaths in RACFs. Conclusion: Future community epidemic wave patterns are unknown but will be major drivers of outcomes in RACFs. Maintaining high coverage of recent vaccination, minimizing incursions, and increasing NPIs can have a major impact on cumulative infections and deaths.

Protein requirements may be lower on a training compared to rest day but are not influenced by moderate training volumes in endurance trained males.

The impact of training volume on protein requirements in endurance trained males was investigated with indicator amino acid oxidation (IAAO) methodology on a recovery day (REST) or after a 10 or 20 km run while consuming a single suboptimal protein intake (0.93 g/kg/day). Phenylalanine excretion (F13CO2; inverse proxy for whole body protein synthesis) was greatest and phenylalanine net balance was lowest on REST compared to post-exercise recovery with no difference between training volumes. Single point F13CO2 was indistinguishable from past IAAO studies using multiple protein intakes. Our results suggest that protein requirements may be greatest on recovery days but are not influenced by moderate training volumes in endurance athletes.

Adapting to compromised routines: Parental perspectives on physical activity and health for children and adolescents with type 1 diabetes in the UK during COVID-19 lockdown.

PURPOSE: To determine how COVID-19 lockdown impacted physical activity (PA) levels, wellbeing, and diabetes management in children (aged 0-17 years) with type 1 diabetes (T1D), from the perspectives of their parent/guardian. DESIGN AND METHODS: This qualitative descriptive study is part of a larger, parallel mixed-methods design study, which incorporated a cross-sectional survey and semi-structured one-to-one interviews. Interviewees were recruited from the survey, which was distributed to parents of children/adolescents with T1D in the UK. Interviews explored diabetes management, mental and physical wellbeing, changes in PA levels, sleep quality before/during lockdown, and the effects of lockdown on the individual and their family. The interviews were transcribed and the data were analysed thematically. RESULTS: 14 interviews were conducted with parents. Thematic analysis generated a central theme of routine disruption, with four further themes on diabetes management routines, harnessing the opportunities of lockdown, weighing up risk, and variable impact on wellbeing. CONCLUSIONS: Maintaining or increasing PA during COVID-19 lockdown was associated with better diabetes management, sleep, and wellbeing for children/adolescents with T1D, despite significant disruption to established routines. Use of technology during the pandemic contributed positively to wellbeing. PRACTICE IMPLICATIONS: It is crucial to emphasize the significance of maintaining a well-structured routine when treating patients with type 1 diabetes. A consistent routine, incorporating regular physical exercise and good sleep hygiene, will help with managing overall diabetes control.

An isolable, chelating bis[cyclic (alkyl)(amino)carbene] stabilizes a strongly bent, dicoordinate Ni(0) complex.

Chelating ligands have had a tremendous impact in coordination chemistry and catalysis. Notwithstanding their success as strongly σ-donating and π-accepting ligands, to date no chelating bis[cyclic (alkyl)(amino)carbenes] have been reported. Herein, we describe a chelating, C2-symmetric bis[cyclic (alkyl)(amino)carbene] ligand, which was isolated as a racemic mixture. The isolation and structural characterization of its isostructural, pseudotetrahedral complexes with iron, cobalt, nickel, and zinc dihalides featuring eight-membered metallacycles demonstrates the binding ability of the bis(carbene). Reduction of the nickel(II) dibromide with potassium graphite produces a dicoordinate nickel(0) complex that features one of the narrowest angles measured in any unsupported dicoordinate transition metal complexes.

The metabolome as a diagnostic for maximal aerobic capacity during exercise in type 1 diabetes.

AIMS/HYPOTHESIS: Our aim was to characterise the in-depth metabolic response to aerobic exercise and the impact of residual pancreatic beta cell function in type 1 diabetes. We also aimed to use the metabolome to distinguish individuals with type 1 diabetes with reduced maximal aerobic capacity in exercise defined by V ˙ O 2peak . METHODS: Thirty participants with type 1 diabetes (≥3 years duration) and 30 control participants were recruited. Groups did not differ in age or sex. After quantification of peak stimulated C-peptide, participants were categorised into those with undetectable (<3 pmol/l), low (3-200 pmol/l) or high (>200 pmol/l) residual beta cell function. Maximal aerobic capacity was assessed by V ˙ O 2peak test and did not differ between control and type 1 diabetes groups. All participants completed 45 min of incline treadmill walking (60% V ˙ O 2peak ) with venous blood taken prior to exercise, immediately post exercise and after 60 min recovery. Serum was analysed using targeted metabolomics. Metabolomic data were analysed by multivariate statistics to define the metabolic phenotype of exercise in type 1 diabetes. Receiver operating characteristic (ROC) curves were used to identify circulating metabolomic markers of maximal aerobic capacity ( V ˙ O 2peak ) during exercise in health and type 1 diabetes. RESULTS: Maximal aerobic capacity ( V ˙ O 2peak ) inversely correlated with HbA1c in the type 1 diabetes group (r2=0.17, p=0.024). Higher resting serum tricarboxylic acid cycle metabolites malic acid (fold change 1.4, p=0.001) and lactate (fold change 1.22, p=1.23×10-5) differentiated people with type 1 diabetes. Higher serum acylcarnitines (AC) (AC C14:1, F value=12.25, p=0.001345; AC C12, F value=11.055, p=0.0018) were unique to the metabolic response to exercise in people with type 1 diabetes. C-peptide status differentially affected metabolic responses in serum ACs during exercise (AC C18:1, leverage 0.066; squared prediction error 3.07). The malic acid/pyruvate ratio in rested serum was diagnostic for maximal aerobic capacity ( V ˙ O 2peak ) in people with type 1 diabetes (ROC curve AUC 0.867 [95% CI 0.716, 0.956]). CONCLUSIONS/INTERPRETATION: The serum metabolome distinguishes high and low maximal aerobic capacity and has diagnostic potential for facilitating personalised medicine approaches to manage aerobic exercise and fitness in type 1 diabetes.

Implementing a Family-Centered Rounds Intervention Using Novel Mentor-Trios.

BACKGROUND AND OBJECTIVES: Patient and Family Centered I-PASS (PFC I-PASS) emphasizes family and nurse engagement, health literacy, and structured communication on family-centered rounds organized around the I-PASS framework (Illness severity-Patient summary-Action items-Situational awareness-Synthesis by receiver). We assessed adherence, safety, and experience after implementing PFC I-PASS using a novel "Mentor-Trio" implementation approach with multidisciplinary parent-nurse-physician teams coaching sites. METHODS: Hybrid Type II effectiveness-implementation study from 2/29/19-3/13/22 with ≥3 months of baseline and 12 months of postimplementation data collection/site across 21 US community and tertiary pediatric teaching hospitals. We conducted rounds observations and surveyed nurses, physicians, and Arabic/Chinese/English/Spanish-speaking patients/parents. RESULTS: We conducted 4557 rounds observations and received 2285 patient/family, 1240 resident, 819 nurse, and 378 attending surveys. Adherence to all I-PASS components, bedside rounding, written rounds summaries, family and nurse engagement, and plain language improved post-implementation (13.0%-60.8% absolute increase by item), all P < .05. Except for written summary, improvements sustained 12 months post-implementation. Resident-reported harms/1000-resident-days were unchanged overall but decreased in larger hospitals (116.9 to 86.3 to 72.3 pre versus early- versus late-implementation, P = .006), hospitals with greater nurse engagement on rounds (110.6 to 73.3 to 65.3, P < .001), and greater adherence to I-PASS structure (95.3 to 73.6 to 72.3, P < .05). Twelve of 12 measures of staff safety climate improved (eg, "excellent"/"very good" safety grade improved from 80.4% to 86.3% to 88.0%), all P < .05. Patient/family experience and teaching were unchanged. CONCLUSIONS: Hospitals successfully used Mentor-Trios to implement PFC I-PASS. Family/nurse engagement, safety climate, and harms improved in larger hospitals and hospitals with better nurse engagement and intervention adherence. Patient/family experience and teaching were not affected.

The relative effectiveness of three and four doses of COVID-19 vaccine in Victoria, Australia: A data linkage study.

BACKGROUND: The Coronavirus Disease 2019 (COVID-19) pandemic led to extensive vaccination campaigns worldwide, including in Australia. Immunity waning and the emergence of new viral variants pose challenges to the effectiveness of vaccines. Our study aimed to assess the relative effectiveness (rVE) of 3 and 4 compared with 2 doses of COVID-19 vaccine. The study focuses on the Victorian population, a majority of whom had no prior exposure to the virus before vaccination. METHODS: We used routinely collected data for the state of Victoria, Australia, to assess rVE during an Omicron-dominant period, 1 June 2022 to 1 March 2023. Immunisation, notifications, hospitalisations and mortality data for residents aged 65 years and older were linked for analysis. Cox proportional hazard regression was used to estimate the rVE against COVID-19 hospitalisation or death, accounting for key confounders with vaccination as a time-varying covariate. RESULTS: In 1,070,113 people 65 years or older who had received their second dose, a third and fourth dose of a COVID-19 vaccine significantly reduced the hazard of hospitalisation or death compared to two doses. rVE was highest within two weeks from administration at 40 % (95 % CI: 0 % to 64 %) and 66 % (95 % CI: 60 % to 71 %) for a third and fourth dose, respectively. Additional protection conferred by third and fourth doses waned over time from administration. CONCLUSIONS: Our findings underscore the need for additional vaccine doses and updated vaccine strategies. These findings have implications for public health advice and COVID-19 vaccine strategies. Further research and monitoring of vaccine effectiveness in real-world settings are warranted to inform ongoing pandemic response efforts.

High intensity interval training as a novel treatment for impaired awareness of hypoglycaemia in people with type 1 diabetes (HIT4HYPOS): a randomised parallel-group study.

AIMS/HYPOTHESIS: Impaired awareness of hypoglycaemia (IAH) in type 1 diabetes may develop through a process referred to as habituation. Consistent with this, a single bout of high intensity interval exercise as a novel stress stimulus improves counterregulatory responses (CRR) to next-day hypoglycaemia, referred to as dishabituation. This longitudinal pilot study investigated whether 4 weeks of high intensity interval training (HIIT) has sustained effects on counterregulatory and symptom responses to hypoglycaemia in adults with type 1 diabetes and IAH. METHODS: HIT4HYPOS was a single-centre, randomised, parallel-group study. Participants were identified using the Scottish Diabetes Research Network (SDRN) and from diabetes outpatient clinics in NHS Tayside, UK. The study took place at the Clinical Research Centre, Ninewells Hospital and Medical School, Dundee, UK. Participants were aged 18-55 years with type 1 diabetes of at least 5 years' duration and HbA1c levels <75 mmol/mol (<9%). They had IAH confirmed by a Gold score ≥4, modified Clarke score ≥4 or Dose Adjustment For Normal Eating [DAFNE] hypoglycaemia awareness rating of 2 or 3, and/or evidence of recurrent hypoglycaemia on flash glucose monitoring. Participants were randomly allocated using a web-based system to either 4 weeks of real-time continuous glucose monitoring (RT-CGM) or RT-CGM+HIIT. Participants and investigators were not masked to group assignment. The HIIT programme was performed for 20 min on a stationary exercise bike three times a week. Hyperinsulinaemic-hypoglycaemic (2.5 mmol/l) clamp studies with assessment of symptoms, hormones and cognitive function were performed at baseline and after 4 weeks of the study intervention. The predefined primary outcome was the difference in hypoglycaemia-induced adrenaline (epinephrine) responses from baseline following RT-CGM or RT-CGM+HIIT. RESULTS: Eighteen participants (nine men and nine women) with type 1 diabetes (median [IQR] duration 27 [18.75-32] years) and IAH were included, with nine participants randomised to each group. Data from all study participants were included in the analysis. During the 4 week intervention there were no significant mean (SEM) differences between RT-CGM and RT-CGM+HIIT in exposure to level 1 (28 [7] vs 22 [4] episodes, p=0.45) or level 2 (9 [3] vs 4 [1] episodes, p=0.29) hypoglycaemia. The CGM-derived mean glucose level, SD of glucose and glucose management indicator (GMI) did not differ between groups. During the hyperinsulinaemic-hypoglycaemic clamp studies, mean (SEM) change from baseline was greater for the noradrenergic responses (RT-CGM vs RT-CGM+HIIT: -988 [447] vs 514 [732] pmol/l, p=0.02) but not the adrenergic responses (-298 [687] vs 1130 [747] pmol/l, p=0.11) in those participants who had undergone RT-CGM+HIIT. There was a benefit of RT-CGM+HIIT for mean (SEM) change from baseline in the glucagon CRR to hypoglycaemia (RT-CGM vs RT-CGM+HIIT: 1 [4] vs 16 [6] ng/l, p=0.01). Consistent with the hormone response, the mean (SEM) symptomatic response to hypoglycaemia (adjusted for baseline) was greater following RT-CGM+HIIT (RT-CGM vs RT-CGM+HIIT: -4 [2] vs 0 [2], p<0.05). CONCLUSIONS/INTERPRETATION: In this pilot clinical trial in people with type 1 diabetes and IAH, we found continuing benefits of HIIT for overall hormonal and symptomatic CRR to subsequent hypoglycaemia. Our findings also suggest that HIIT may improve the glucagon response to insulin-induced hypoglycaemia. TRIAL REGISTRATION: ISRCTN15373978. FUNDING: Sir George Alberti Fellowship from Diabetes UK (CMF) and the Juvenile Diabetes Research Foundation.

Effectiveness of community-based oral antiviral treatments against severe COVID-19 outcomes in people 70 years and over in Victoria, Australia, 2022: an observational study.

Background: Oral Antiviral (OAV) COVID-19 treatments are widely used, but evidence for their effectiveness against the Omicron variant in higher risk, vaccinated individuals is limited. Methods: Retrospective study of two vaccinated cohorts of COVID-19 cases aged ≥70 years diagnosed during a BA.4/5 Omicron wave in Victoria, Australia. Cases received either nirmatrelvir-ritonavir or molnupiravir as their only treatment. Data linkage and logistic regression modelling was used to evaluate the association between treatment and death and hospitalisation and compared with no treatment. Findings: Of 38,933 individuals in the mortality study population, 13.5% (n = 5250) received nirmatrelvir-ritonavir, 51.3% (n = 19,962) received molnupiravir and 35.2% (n = 13,721) were untreated. Treatment was associated with a 57% (OR = 0.43, 95% CI 0.36-0.51) reduction in the odds of death, 73% (OR = 0.27, 95% CI 0.17-0.40) for nirmatrelvir-ritonavir and 55% (OR = 0.45, 95% CI 0.38-0.54) for molnupiravir. Treatment was associated with a 31% (OR = 0.69, 95% CI 0.55-0.86) reduction in the odds of hospitalisation, 40% (OR = 0.60, 95% CI 0.43-0.83) for nirmatrelvir-ritonavir and 29% (OR = 0.71, 95% CI 0.58-0.87) for molnupiravir. Cases treated within 1 day of diagnosis had a 61% reduction in the odds of death (OR = 0.39, 95% CI 0.33-0.46) compared with 33% reduction for a delay of 4 or more days (OR = 0.67, 95% CI 0.44-0.97). Interpretation: Treatment with both nirmatrelvir-ritonavir or molnupiravir was associated with a reduction in death and hospitalisation in vaccinated ≥70 years individuals during the Omicron era. Timely, equitable treatment with OAVs is an important tool in the fight against COVID-19. Funding: There was no funding for this study.

Protein Requirements Are Increased in Endurance-Trained Athletes but Similar between Females and Males during Postexercise Recovery.

PURPOSE: This study aimed to determine the daily protein requirements of female and male endurance athletes in a home-based setting using noninvasive stable isotope methodology (i.e., indicator amino acid oxidation). METHODS: Eight males (30 ± 3 yr; 78.6 ± 10.5 kg; 75.6 ± 7.5 mL·kgFFM-1·min-1; mean ± SD) and seven females (30 ± 4 yr; 57.7 ± 5.0 kg; 77.5 ± 7.1 mL·kgFFM-1·min-1) during the midluteal phase were studied. After 2 d of controlled diet (1.4 gprotein·kg-1·d-1) and training (10 and 5 km run·d-1, respectively), participants completed a 20-km run before an at-home indicator amino acid oxidation trial testing a suboptimal, a moderate, and an excess (i.e., 0.2, 1.2, and 2.0 g·kg-1·d-1, respectively) protein intake. Protein was consumed as a crystalline amino acid mixture containing [1-13C]phenylalanine to examine whole-body phenylalanine flux and phenylalanine oxidation (PheOx; the reciprocal of whole-body protein synthesis) through breath and urine sample collection. A modified biphasic linear regression determined the breakpoint in PheOx for each participant to generate an estimated average intake that would maximize whole-body protein synthesis for each sex. RESULTS: PheOx was different (P < 0.01) between all protein intakes with no effect of sex (P = 0.63). Using a modified three-point curve resulted in a breakpoint that was not different (P = 0.94) between males and females (1.60 and 1.61 g·kg-1·d-1, respectively). The recommended intake (i.e., upper 95% confidence interval) was estimated to be 1.81 and 1.89 g·kg-1·d-1 for males and females, respectively. CONCLUSIONS: Our findings indicate that endurance athletes consuming a daily protein intake toward the upper end of current consensus recommendations (~1.85 g·kg-1·d-1) will maximize whole-body protein synthesis during postexercise recovery regardless of sex.

Recommendations from Diabetes UK's 2022 diabetes and physical activity workshop.

AIMS: To describe the process and outputs of a workshop convened to identify key priorities for future research in the area of diabetes and physical activity and provide recommendations to researchers and research funders on how best to address them. METHODS: A 1-day research workshop was conducted, bringing together researchers, people living with diabetes, healthcare professionals, and members of staff from Diabetes UK to identify and prioritise recommendations for future research into physical activity and diabetes. RESULTS: Workshop attendees prioritised four key themes for further research: (i) better understanding of the physiology of exercise in all groups of people: in particular, what patient metabolic characteristics influence or predict the physiological response to physical activity, and the potential role of physical activity in beta cell preservation; (ii) designing physical activity interventions for maximum impact; (iii) promoting sustained physical activity across the life course; (iv) designing physical activity studies for groups with multiple long-term conditions. CONCLUSIONS: This paper outlines recommendations to address the current gaps in knowledge related to diabetes and physical activity and calls on the research community to develop applications in these areas and funders to consider how to stimulate research in these areas.

Reliability and minimal detectable difference of pressure pain thresholds in a pain-free population.

The objective of this work was to evaluate the inter-rater and intra-rater reliability and minimal detectable difference (MDD) of pressure pain thresholds (PPTs) in pain-free participants with two examiners over two consecutive days in a cross-sectional study design. Examiners used a standardized method to measure and locate a specific testing site over tibialis anterior for PPT testing with a hand-held algometer. The mean of each examiner's three PPT measurements was used to calculate the intraclass correlation coefficient, inter-rater reliability, and intra-rater reliability. The minimal detectable difference (MDD) was calculated. Eighteen participants were recruited (11 female). The inter-rater reliability was 0.94 and 0.96 on day 1 and day 2, respectively. Intra-rater reliability for the examiners was 0.96 and 0.92 on day 1 and day 2, respectively. The MDD on day 1 was 1.24 kg/cm2 (CI: 0.76-2.03) and the MDD on day 2 was 0.88 kg/cm2 (CI: 0.54-1.43). This study demonstrates high inter- and intra-rater reliability and the MDD values for this method of pressure algometry.

COVID-19 epidemic modelling for policy decision support in Victoria, Australia 2020-2021.

BACKGROUND: Policy responses to COVID-19 in Victoria, Australia over 2020-2021 have been supported by evidence generated through mathematical modelling. This study describes the design, key findings, and process for policy translation of a series of modelling studies conducted for the Victorian Department of Health COVID-19 response team during this period. METHODS: An agent-based model, Covasim, was used to simulate the impact of policy interventions on COVID-19 outbreaks and epidemic waves. The model was continually adapted to enable scenario analysis of settings or policies being considered at the time (e.g. elimination of community transmission versus disease control). Model scenarios were co-designed with government, to fill evidence gaps prior to key decisions. RESULTS: Understanding outbreak risk following incursions was critical to eliminating community COVID-19 transmission. Analyses showed risk depended on whether the first detected case was the index case, a primary contact of the index case, or a 'mystery case'. There were benefits of early lockdown on first case detection and gradual easing of restrictions to minimise resurgence risk from undetected cases. As vaccination coverage increased and the focus shifted to controlling rather than eliminating community transmission, understanding health system demand was critical. Analyses showed that vaccines alone could not protect health systems and need to be complemented with other public health measures. CONCLUSIONS: Model evidence offered the greatest value when decisions needed to be made pre-emptively, or for questions that could not be answered with empiric data and data analysis alone. Co-designing scenarios with policy-makers ensured relevance and increased policy translation.