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.

Considering impact of age and sex on cardiac cytoskeletal components.

The cardiac cytoskeletal components are integral to cardiomyocyte function and are responsible for contraction, sustaining cell structure, and providing scaffolding to direct signaling. Cytoskeletal components have been implicated in cardiac pathology; however, less attention has been paid to age-related modifications of cardiac cytoskeletal components and how these contribute to dysfunction with increased age. Moreover, significant sex differences in cardiac aging have been identified, but we still lack a complete understanding to the mechanisms behind these differences. This review summarizes what is known about how key cardiomyocyte cytoskeletal components are modified because of age, as well as reported sex-specific differences. Thorough consideration of both age and sex as integral players in cytoskeletal function may reveal potential avenues for more personalized therapeutics.

Slow rewarming after hypothermia does not ameliorate white matter injury after hypoxia-ischemia in near-term fetal sheep.

BACKGROUND: The optimal rate to rewarm infants after therapeutic hypothermia is unclear. In this study we examined whether slow rewarming after 72 h of hypothermia would attenuate white matter injury. METHODS: Near-term fetal sheep received sham occlusion (n = 8) or cerebral ischemia for 30 min, followed by normothermia (n = 7) or hypothermia from 3-72 h, with either spontaneous fast rewarming (n = 8) within 1 h, or slow rewarming at ~0.5 °C/h (n = 8) over 10 h. Fetuses were euthanized 7 days later. RESULTS: Ischemia was associated with loss of total and mature oligodendrocytes, reduced expression of myelin proteins and induction of microglia and astrocytes, compared with sham controls (P < 0.05). Both hypothermia protocols were associated with a significant increase in numbers of total and mature oligodendrocytes, area fraction of myelin proteins and reduced numbers of microglia and astrocytes, compared with ischemia-normothermia (P < 0.05). There was no difference in the number of oligodendrocytes, microglia or astrocytes or expression of myelin proteins between fast and slow rewarming after hypothermia. CONCLUSION: The rate of rewarming after a clinically relevant duration of hypothermia had no apparent effect on white matter protection by hypothermia after cerebral ischemia in near-term fetal sheep. IMPACT: Persistent white matter injury is a major contributor to long-term disability after neonatal encephalopathy despite treatment with therapeutic hypothermia. The optimal rate to rewarm infants after therapeutic hypothermia is unclear; current protocols were developed on a precautionary basis. We now show that slow rewarming at 0.5 °C/h did not improve histological white matter injury compared with rapid spontaneous rewarming after a clinically established duration of hypothermia in near-term fetal sheep.

The influence of estrogen on myocardial post-translational modifications and cardiac function in women.

The lifetime risk of heart failure (HF) is comparable in men and women; nevertheless, disparities exist in our understanding of how HF differs between sexes. Several differences in cardiac physiology exist between men and women including the propensity to develop specific HF phenotypes. Men are more likely to be diagnosed with HF failure with reduced ejection fraction, while women have a greater propensity to develop HF with preserved ejection fraction. The mechanisms responsible for these differences remain unclear. Post-translational modifications (PTMs) of myofilament proteins likely contribute to these sex-specific propensities. The role of PTMs in heart disease is an expanding field with immense potential therapeutic targets. However, numerous PTMs remain underexplored, particularly in the context of the female heart. Estrogen, a key gonadal hormone, cardioprotective in pre-menopausal women and its loss with menopause likely contributes to disease in aging women. However, how estrogen regulates PTMs to contribute to HF development is not fully clear. This review outlines key sex differences in HF along with characterizing the contributions of novel myocardial PTMs in cardiac physiology and their regulation by estrogen. Collectively, we highlight the necessity for further investigation into women's heart health and the distinctive mechanisms distinguishing women from men.

Benefits, implementation and sustainability of innovative paediatric models of care for children with type 1 diabetes: a systematic review.

BACKGROUND AND AIM: The evidence about the acceptability and effectiveness of innovative paediatric models of care for Type 1 diabetes is limited. To address this gap, we synthesised literature on implemented models of care, model components, outcomes, and determinants of implementation and sustainability. METHODS: A systematic review was conducted and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Database searches of Medline, CINAHL, EMBASE and Scopus were conducted. Empirical studies focused on Type 1 diabetes paediatric models of care, published from 2010 to 2022 in English were included. RESULTS: Nineteen extant studies reported on models and their associations with health and psychosocial outcomes, patient engagement with healthcare, and healthcare costs. Thirteen studies described multidisciplinary teamwork, education and capacity building that supported self-care. Four studies involved shared decision making between providers and patients, and two discussed outreach support where technology was an enabler. Fourteen studies reported improvements in health outcomes (e.g. glycaemic control), mostly for models that included multidisciplinary teams, education, and capacity building (11 studies), outreach support or shared care (3 studies). Four studies reported improvements in quality of life, three reported increased satisfaction for patients and carers and, and one reported improved communication. Four of five studies describing shared care and decision-making reported improvements in quality of life, support and motivation. Outreach models reported no negative outcomes, however, accessing some models was limited by technological and cost barriers. Eight studies reported on model sustainability, but only half reported implementation determinants; none reported applying a theoretical framework to guide their research. CONCLUSION: Some health and psychosocial benefits were associated with newer models. To address knowledge gaps about implementation determinants and model sustainability, longitudinal studies are needed to inform future adoption of innovative models of care for children with Type 1 diabetes.

Evaluation of Critical Care Pharmacist Evening Services at an Academic Medical Center.

Purpose: Critical care pharmacists are considered essential members of the healthcare team; however, justification and recruitment of new positions, especially in the evening or weekend shifts, remains a significant challenge. The purpose of this study was to investigate the number of interventions, type of interventions, and associated cost savings with the addition of 1 board certified critical care clinical pharmacist to evening shift. Methods: This was a prospective collection and characterization of 1 evening shift critical care pharmacist's clinical interventions over a 12-week period. Interventions were collected and categorized daily from 13:00 to 22:00 Monday through Friday. After collection was complete, cost savings estimates were calculated using pharmacy wholesaler acquisition cost. Results: Interventions were collected on 52 of 60 weekdays. A total of 510 interventions were collected with an average of 9.8 interventions accepted per day. The most common interventions included transitions of care, medication dose adjustment, and antibiotic de-escalation and the highest proportion of interventions occurred in the medical intensive care unit. An estimated associated cost avoidance of $66 537.80 was calculated for an average of $1279.57 saved per day. Additionally, 22 (4.1%) of interventions were considered high yield interventions upon independent review by 2 pharmacists. Conclusion: The addition of 1 board-certified critical care pharmacist to evening shift resulted in multiple interventions across several categories and a significant cost avoidance when calculated using conservative measures.

Socioeconomic representativeness of Australian, Canadian and British cohorts from the paediatric diabetes AdDIT study: comparisons to regional and national data.

BACKGROUND: Given limited data regarding the involvement of disadvantaged groups in paediatric diabetes clinical trials, this study aimed to evaluate the socioeconomic representativeness of participants recruited into a multinational clinical trial in relation to regional and national type 1 diabetes reference populations. METHODS: Retrospective, cross-sectional evaluation of a subset of adolescent type 1 diabetes cardiorenal intervention trial (AdDIT) participants from Australia (n = 144), Canada (n = 312) and the UK (n = 173). Validated national measures of deprivation were used: the Index of Relative Socioeconomic Disadvantage (IRSD) 2016 (Australia), the Material Resources (MR) dimension of the Canadian Marginalisation index 2016 (Canada) and the Index of Multiple Deprivation (IMD) 2015 (UK). Representativeness was assessed by comparing the AdDIT cohort's distribution of deprivation quintiles with that of the local paediatric type 1 diabetes population (regional), and the broader type 1 diabetes population for which the trial's intervention was targeted (national). RESULTS: Recruited study cohorts from each country had higher proportions of participants with higher SES, and significant underrepresentation of lower SES, in relation to their national references. The socioeconomic make-up in Australia mirrored that of the regional population (p = 0.99). For Canada, the 2nd least deprived (p = 0.001) and the most deprived quintiles (p < 0.001) were over- and under-represented relative to the regional reference, while the UK featured higher regional and national SES bias with over-representation and under-representation from the least-deprived and most-deprived quintiles (p < 0.0001). CONCLUSIONS: Significant national differences in trial participation of low SES participants were observed, highlighting limitations in access to clinical research and the importance of reporting sociodemographic representation in diabetes clinical trials. TRIAL REGISTRATION: NCT01581476. Registered on 20 April 2012.

Plasma matrix metalloproteinase-3 predicts mortality in acute respiratory distress syndrome: a biomarker analysis of a randomized controlled trial.

BACKGROUND: Matrix metalloproteinase-3 (MMP-3) is a proteolytic enzyme involved in acute respiratory distress syndrome (ARDS) pathophysiology that may serve as a lung-specific biomarker in ARDS. METHODS: This study was a secondary biomarker analysis of a subset of Albuterol for the Treatment of Acute Lung Injury (ALTA) trial patients to determine the prognostic value of MMP-3. Plasma sample MMP-3 was measured by enzyme-linked immunosorbent assay. The primary outcome was the area under the receiver operating characteristic (AUROC) of MMP-3 at day 3 for the prediction of 90-day mortality. RESULTS: A total of 100 unique patient samples were evaluated and the AUROC analysis of day three MMP-3 showed an AUROC of 0.77 for the prediction of 90-day mortality (95% confidence interval: 0.67-0.87), corresponding to a sensitivity of 92% and specificity of 63% and an optimal cutoff value of 18.4 ng/mL. Patients in the high MMP-3 group (≥ 18.4 ng/mL) showed higher mortality compared to the non-elevated MMP-3 group (< 18.4 ng/mL) (47% vs. 4%, p < 0.001). A positive difference in day zero and day three MMP-3 concentration was predictive of mortality with an AUROC of 0.74 correlating to 73% sensitivity, 81% specificity, and an optimal cutoff value of + 9.5 ng/mL. CONCLUSIONS: Day three MMP-3 concentration and difference in day zero and three MMP-3 concentrations demonstrated acceptable AUROCs for predicting 90-day mortality with a cut-point of 18.4 ng/mL and + 9.5 ng/mL, respectively. These results suggest a prognostic role of MMP-3 in ARDS.

Reproducibility of plasma glucose responses to moderate-intensity exercise in individuals with type 1 diabetes.

AIM: To examine the within-person variability in plasma glucose responses to moderate-intensity morning exercise in young individuals with type 1 diabetes after overnight fasting and under basal insulin conditions. METHODS: In this pilot study, eight participants completed 40 min of moderate-intensity exercise at 60% V̇O2 peak on three separate days. The within-person standard deviation (SDw) in plasma glucose response was analysed both during and 1 h after exercise using the two visits per participant most closely matched by pre-exercise plasma glucose level. RESULTS: When the two closest matched visits per individual were included for analysis, mean (±SD) change in plasma glucose level was -1.8 ± 1.1 mmoL/L during exercise and -0.6 ± 1.0 mmoL/L during recovery, with the SDw of these changes being 0.5 mmol (95% CI 0.2, 0.8) during exercise and 0.8 mmoL/L (95% CI 0.4, 1.3) during recovery. The median intra-individual difference in plasma glucose level change was 0.3 mmoL/L [IQR 0.1, 0.7] during exercise and 0.8 mmoL/L [IQR 0.4, 1.0] during recovery. CONCLUSION: Within-person plasma glucose responses to moderate-intensity exercise may be reproducible under fasting and basal insulin conditions and similar pre-exercise plasma glucose levels. This finding may assist the design of future studies investigating both the reproducibility of glycaemic responses to exercise and blood glucose management for individuals with type 1 diabetes.

Early and Increased Influenza Activity Among Children - Tennessee, 2022-23 Influenza Season.

Influenza seasons typically begin in October and peak between December and February (1); however, the 2022-23 influenza season in Tennessee began in late September and was characterized by high pediatric hospitalization rates during November. This report describes a field investigation conducted in Tennessee during November 2022, following reports of increasing influenza hospitalizations. Data from surveillance networks, patient surveys, and whole genome sequencing of influenza virus specimens were analyzed to assess influenza activity and secondary illness risk. Influenza activity increased earlier than usual among all age groups, and rates of influenza-associated hospitalization among children were high in November, reaching 12.6 per 100,000 in children aged <5 years, comparable to peak levels typically seen in high-severity seasons. Circulating influenza viruses were genetically similar to vaccine components. Among persons who received testing for influenza at outpatient clinics, children were twice as likely to receive a positive influenza test result as were adults. Among household contacts exposed to someone with influenza, children were more than twice as likely to become ill compared with adults. As the influenza season continues, it is important for all persons, especially those at higher risk for severe disease, to protect themselves from influenza. To prevent influenza and severe influenza complications, all persons aged ≥6 months should get vaccinated, avoid contact with ill persons, and take influenza antivirals if recommended and prescribed.

An assessment of the downstream implications of blood culture collection and transit.

The implications of the variables within the pre-analytical phase of blood culture processing are poorly understood. This study aims to explore the effect of transit times (TT) and culture volume, on time to microbiological diagnosis and patient outcomes. Blood cultures received between 1st March and 31st July 2020/21 were identified. TT, time in incubator (TII), and for positive samples, request to positivity times (RPT) were calculated. Demographic details were recorded for all samples, and culture volume, length of stay (LoS), and 30-day mortality for patients with positive samples. Statistical analysis examined how culture volume and TT effected culture positivity and outcome; in the context of the 4-h national TT target. Totally, 14,375 blood culture bottles were received from 7367 patients; 988 (13.4%) were positive for organisms. There was no significant difference between TT of negative and positive samples. The RPT was significantly lower for samples with TT < 4 h (p < 0.001). Culture bottle volume did not affect RPT (p = 0.482) or TII (p = 0.367). A prolonged TT was associated with a longer length-of-stay in those with a bacteraemia with a significant organism (p = 0.001). We found shorter blood culture transportation time was associated with a significantly faster time of positive culture reporting, while optimal blood culture volume did not make a significant impact. Delays in reporting for significant organisms correspond to a prolonged LoS. Laboratory centralisation makes achieving the 4-h target a logistical challenge; however, this data suggests such targets have significant microbiological and clinical impacts.

Glycaemic outcomes in Australasian children and adults with type 1 diabetes: failure to meet targets across the age spectrum.

BACKGROUND: The goal of therapy in type 1 diabetes (T1D) is to achieve optimal glycaemic targets and reduce complications. Robust data representing glycaemic outcomes across the lifespan are lacking in Australasia. AIMS: To examine contemporary glycaemic outcomes and rate of use of diabetes technologies in Australasian people with T1D. METHODS: Cross-sectional analysis of de-identified data from 18 diabetes centres maintained in the Australasian Diabetes Data Network registry during 2019. Glycaemia was measured using glycated haemoglobin (HbA1c). The proportion of people with T1D achieving the international HbA1c target of <53 mmol/mol (7%) was calculated. Rates of continuous subcutaneous insulin infusion (CSII) and continuous glucose monitoring (CGM) use were determined. RESULTS: A total of 7988 individuals with T1D with 30 575 visits were recorded in the registry. The median (interquartile range) age was 15.3 (10.0) years and diabetes duration was 5.7 (9.4) years with 49% on multiple daily injections (MDI) and 36% on CSII. The mean HbA1c for the whole cohort was 66 mmol/mol (8.2%). HbA1c increased with age, from 60 mmol/mol (7.6%) in children <10 years, increasing during adolescence and peaking at 73 mmol/mol (8.8%) in the 20-25 years age group. The HbA1c target of <53 mmol/mol (7%) was met in 18% of children and 13% of adults. HbA1c was lower on CSII as compared with those on MDI (P < 0.0001). CONCLUSIONS: Only a minority of children and adults achieve the recommended glycaemic goals despite access to specialist care in major diabetes centres. There is a need to identify factors that improve glycaemic outcomes.

Transition models of care for type 1 diabetes: a systematic review.

BACKGROUND: Managing the care regimen for Type 1 Diabetes is challenging for emerging adults, as they take on greater responsibility for self-management. A diverse range of models of care have been implemented to improve safety and quality of care during transition between paediatric and adult services. However, evidence about acceptability and effectiveness of these is limited. Our aim was to synthesise the evidence for transition models and their components, examine the health related and psychosocial outcomes, and to identify determinants associated with the implementation of person-centred models of transition care. METHOD: We searched Medline, CINAHL, EMBASE and Scopus. Peer reviewed empirical studies that focused on T1D models of care published from 2010 to 2021 in English, reporting experimental, qualitative, mixed methods, and observational studies were included. RESULTS: Fourteen studies reported on health and psychosocial outcomes, and engagement with healthcare. Three key models of care emerged: structured transition education programs (6 studies), multidisciplinary team transition support (5 studies) and telehealth/virtual care (3 studies). Compared with usual practice, three of the six structured transition education programs led to improvements in maintenance of glycaemic control, psychological well-being, and engagement with health services. Four MDT transition care models reported improved health outcomes, and improved engagement with health services, however, three studies reported no benefit. Reduced diabetes related stress and increased patient satisfaction were reported by two studies, but three reported no benefit. Telehealth and virtual group appointments improved adherence to self-management and reduced diabetes distress but did not change health outcomes. CONCLUSIONS: Although some health and psychosocial benefits are reported, the results were mixed. No studies reported on T1D transition model implementation outcomes such as acceptability, adoption, and appropriateness among clinicians or managers implementing these models. This gap needs to be addressed to support future adoption of successful models.

Pulmonary artery banding: still a role for staged bi-ventricular repair of intracardiac shunts?

OBJECTIVES: Although pulmonary artery banding remains a useful palliation in bi-ventricular shunting lesions, single-stage repair holds several advantages. We investigate outcomes of the former approach in high-risk patients. METHODS: Retrospective cohort study including all pulmonary artery banding procedures over 9 years, excluding single ventricle physiology and left ventricular training. RESULTS: Banding was performed in 125 patients at a median age of 41 days (2-294) and weight of 3.4 kg (1.8-7.32). Staged repair was undertaken for significant co-morbidity in 81 (64.8%) and anatomical complexity in 44 (35.2%). The median hospital stay was 14 days (interquartile range 8-33.5) and 14 patients (11.2%) required anatomical repair before discharge. Nine patients died during the initial admission (hospital mortality 7.2 %) and five following discharge (inter-stage mortality 4.8%). Of 105 banded patients who survived, 19 (18.1%) needed inter-stage re-admission and 18 (14.4%) required unplanned re-intervention. Full repair was performed in 93 (74.4%) at a median age of 13 months (3.1-49.9) and weight of 8.5 kg (3.08-16.8). Prior banding, 54% were below the 0.4th weight centile, but only 28% remained so at repair. Post-repair, 5/93 (5.4%) developed heart block requiring permanent pacemaker, and 11/93 (11.8%) required unplanned re-intervention. The post-repair mortality (including repairs during the initial admission) was 6/93 (6.5%), with overall mortality of the staged approach 13.6% (17/125). CONCLUSIONS: In a cohort with a high incidence of co-morbidity, pulmonary artery banding is associated with a significant risk of re-intervention and mortality. Weight gain improves after banding, but heart block, re-intervention, and mortality remain frequent following repair.

Feasibility of non-invasive neuro-monitoring during extracorporeal membrane oxygenation in children.

INTRODUCTION: Detection of neurological complications during extracorporeal membrane oxygenation (ECMO) may be enhanced with non-invasive neuro-monitoring. We investigated the feasibility of non-invasive neuro-monitoring in a paediatric intensive care (PIC) setting. METHODS: In a single centre, prospective cohort study we assessed feasibility of recruitment, and neuro-monitoring via somatosensory evoked potentials (SSEP), electroencephalography (EEG) and near infrared spectroscopy (NIRS) during venoarterial (VA) ECMO in paediatric patients (0-15 years). Measures were obtained within 24h of cannulation, during an intermediate period, and finally at decannulation or echo stress testing. SSEP/EEG/NIRS measures were correlated with neuro-radiology findings, and clinical outcome assessed via the Pediatric cerebral performance category (PCPC) scale 30 days post ECMO cannulation. RESULTS: We recruited 14/20 (70%) eligible patients (median age: 9 months; IQR:4-54, 57% male) over an 18-month period, resulting in a total of 42 possible SSEP/EEG/NIRS measurements. Of these, 32/42 (76%) were completed. Missed recordings were due to lack of access/consent within 24 h of cannulation (5/42, 12%) or PIC death/discharge (5/42, 12%). In each patient, the majority of SSEP (8/14, 57%), EEG (8/14, 57%) and NIRS (11/14, 79%) test results were within normal limits. All patients with abnormal neuroradiology (4/10, 40%), and 6/7 (86%) with poor outcome (PCPC ≥4) developed indirect SSEP, EEG or NIRS measures of neurological complications prior to decannulation. No study-related adverse events or neuro-monitoring data interpreting issues were experienced. CONCLUSION: Non-invasive neuro-monitoring (SSEP/EEG/NIRS) during ECMO is feasible and may provide early indication of neurological complications in this high-risk population.

Urinary albumin/creatinine ratio tertiles predict risk of diabetic retinopathy progression: a natural history study from the Adolescent Cardio-Renal Intervention Trial (AdDIT) observational cohort.

AIMS/HYPOTHESIS: We hypothesised that adolescents with type 1 diabetes with a urinary albumin/creatinine ratio (ACR) in the upper tertile of the normal range (high ACR) are at greater risk of three-step diabetic retinopathy progression (3DR) independent of glycaemic control. METHODS: This was a prospective observational study in 710 normoalbuminuric adolescents with type 1 diabetes from the non-intervention cohorts of the Adolescent Cardio-Renal Intervention Trial (AdDIT). Participants were classified as 'high ACR' or 'low ACR' (lowest and middle ACR tertiles) using baseline standardised log10 ACR. The primary outcome, 3DR, was determined from centrally graded, standardised two-field retinal photographs. 3DR risk was determined using multivariable Cox regression for the effect of high ACR, with HbA1c, BP, LDL-cholesterol and BMI as covariates; diabetes duration was the time-dependent variable. RESULTS: At baseline mean ± SD age was 14.3 ± 1.6 years and mean ± SD diabetes duration was 7.2 ± 3.3 years. After a median of 3.2 years, 83/710 (12%) had developed 3DR. In multivariable analysis, high ACR (HR 2.1 [1.3, 3.3], p=0.001), higher mean IFCC HbA1c (HR 1.03 [1.01, 1.04], p=0.001) and higher baseline diastolic BP SD score (HR 1.43 [1.08, 1.89], p=0.01) were independently associated with 3DR risk. CONCLUSIONS/INTERPRETATION: High ACR is associated with greater risk of 3DR in adolescents, providing a target for future intervention studies. TRIAL REGISTRATION: isrctn.org ISRCTN91419926.

SARS-CoV-2 Outbreak among Malayan Tigers and Humans, Tennessee, USA, 2020.

We report an outbreak of severe acute respiratory syndrome coronavirus 2 involving 3 Malayan tigers (Panthera tigris jacksoni) at a zoo in Tennessee, USA. Investigation identified naturally occurring tiger-to-tiger transmission; genetic sequence change occurred with viral passage. We provide epidemiologic, environmental, and genomic sequencing data for animal and human infections.

Alcohol, smoking, recreational drug use and association with virological outcomes among people living with HIV: cross-sectional and longitudinal analyses.

OBJECTIVES: There is increasing evidence to suggest that people living with HIV (PLWH) have significant morbidity from alcohol, recreational drug use and cigarette smoking. Our aim was to report associations of these factors with antiretroviral therapy (ART) non-adherence, viral non-suppression and subsequent viral rebound in PLWH. METHODS: The Antiretroviral Sexual Transmission Risk and Attitudes (ASTRA) study recruited PLWH attending eight outpatient clinics in England between February 2011 and December 2012. Data included self-reported excessive drinking (estimated consumption of > 20 units of alcohol/week), alcohol dependency (CAGE score ≥ 2 with current alcohol consumption), recreational drug use (including injection drug use in the past 3 months), and smoking status. Among participants established on ART, cross-sectional associations with ART non-adherence [missing ≥2 consecutive days of ART on ≥2 occasions in the past three months] and viral-non suppression [viral load (VL) > 50 copies/mL] were assessed using logistic regression. In participants from one centre, longitudinal associations with subsequent viral rebound (first VL > 200 copies/mL) in those on ART with VL ≤ 50 copies/mL at baseline were assessed using Cox regression during a 7-year follow-up. RESULTS: Among 3258 PLWH, 2248 (69.0%) were men who have sex with men, 373 (11.4%) were heterosexual men, and 637 (19.6%) were women. A CAGE score ≥ 2 was found in 568 (17.6%) participants, 325 (10.1%) drank > 20 units/week, 1011 (31.5%) currently smoked, 1242 (38.1%) used recreational drugs and 74 (2.3%) reported injection drug use. In each case, prevalence was much more common among men than among women. Among 2459 people on ART who started at least 6 months previously, a CAGE score ≥ 2, drinking > 20 units per week, current smoking, injection and non-injection drug use were all associated with ART non-adherence. After adjusting for demographic and socioeconomic factors, CAGE score ≥ 2 [adjusted odds ratio (aOR) = 1.52, 95% confidence interval (CI): 1.09-2.13], current smoking (aOR = 1.58, 95% CI: 1.10-2.17) and injection drug use (aOR = 2.11, 95% CI: 1.00-4.47) were associated with viral non-suppression. During follow-up of a subset of 592 people virally suppressed at recruitment, a CAGE score ≥ 2 [adjusted hazard ratio (aHR) = 1.66, 95% CI: 1.03-2.74], use of 3 or more non-injection drugs (aHR = 1.82, 95% CI: 1.12-3.57) and injection drug use (aHR = 2.73, 95% CI: 1.08-6.89) were associated with viral rebound. CONCLUSIONS: Screening and treatment for alcohol, cigarette and drug use should be integrated into HIV outpatient clinics, while clinicians should be alert to the potential for poorer virological outcomes.

The relationship between meal carbohydrate quantity and the insulin to carbohydrate ratio required to maintain glycaemia is non-linear in young people with type 1 diabetes: A randomized crossover trial.

OBJECTIVE: To determine if the relationship between meal carbohydrate quantity and the insulin to carbohydrate ratio (ICR) required to maintain glycaemia is linear in people with type 1 diabetes. METHODS: We used an open labelled randomized four-arm cross-over study design. Participants (N = 31) aged 12-27 years, HbA1c ≤ 64 mmol/mol (8.0%) received insulin doses based on the individual's ICR and the study breakfast carbohydrate quantity and then consumed four breakfasts containing 20, 50, 100 and 150 g of carbohydrate over four consecutive days in randomized order. The breakfast fat and protein percentages were standardized. Postprandial glycaemia was assessed by 5 h continuous glucose monitoring. The primary outcome was percent time in range (TIR) and secondary outcomes included hypoglycaemia, glucose excursion and incremental area under the curve. Statistical analysis included linear mixed modelling and Wilcoxon signed rank tests. RESULTS: The 20 g carbohydrate breakfast had the largest proportion of TIR (0.74 ± 0.29 p < 0.04). Hypoglycaemia was more frequent in the 50 g (n = 13, 42%) and 100 g (n = 15, 50%) breakfasts compared to the 20 g (n = 6, 20%) and 150 g (n = 7, 26%) breakfasts (p < 0.029). The 150 g breakfast glucose excursion pattern was different from the smaller breakfasts with the lowest glucose excursion 0-2 h and the highest excursion from 3.5 to 5 h. CONCLUSIONS: A non-linear relationship between insulin requirement and breakfast carbohydrate content was observed, suggesting that strengthened ICRs are needed for meals with ≤20 and ≥150 g of carbohydrate. Meals with ≥150 g of carbohydrate may benefit from dual wave bolusing.

Hybrid closed-loop therapy with a first-generation system increases confidence and independence in diabetes management in youth with type 1 diabetes.

AIM: Hybrid closed-loop (HCL) therapy improves glycaemic control in adolescents with type 1 diabetes; however, little is known about their lived experience using these systems. The aim of this study was to explore the lived experiences of youth with type 1 diabetes using HCL therapy, and their parents, to provide insight into their lived experiences. METHODS: Adolescents and young adults aged 12-25 years, who used Medtronic MiniMed™ 670G HCL system during a 6-month randomised clinical trial, and their parents, were invited to participate in a semi-structured interview at the end of the study. Open-ended questions were used to explore the lived experiences of families using HCL. The interviews were audio-recorded, transcribed and analysed using thematic analysis to determine the main themes. RESULTS: In all, 17 young people with type 1 diabetes mean ± SD age: 17.5 ± 4.2 years, diabetes duration: 11.0 ± 4.9 years and HbA1c 64 ± 9 mmol/mol (8.0 ± 0.8%) and 10 parents were interviewed. Three themes were identified: (1) 'Developing confidence and trust in the system', (2) 'Reduction in anxiety' and (3) 'Issues with device'. They reported a positive experience using HCL, with improvements in glucose levels and increased independence with diabetes management. However, frustration around the number of alarms and notifications associated with the system were also identified as issues. CONCLUSION: Both youth and parents acknowledged the benefits of this first-generation HCL system in improving glycaemic outcomes and in providing flexibility and independence. These lived experiences provide valuable information in the introduction and provision of targeted education with HCL therapy.