Photobiomodulation in the infrared spectrum reverses the expansion of circulating natural killer cells and brain microglial activation in Sanfilippo mice.

Sanfilippo syndrome results from inherited mutations in genes encoding lysosomal enzymes that catabolise heparan sulfate (HS), leading to early childhood-onset neurodegeneration. This study explores the therapeutic potential of photobiomodulation (PBM), which is neuroprotective and anti-inflammatory in several neurodegenerative diseases; it is also safe and PBM devices are readily available. We investigated the effects of 10-14 days transcranial PBM at 670 nm (2 or 4 J/cm2/day) or 904 nm (4 J/cm2/day) in young (3 weeks) and older (15 weeks) Sanfilippo or mucopolysaccharidosis type IIIA (MPS IIIA) mice. Although we found no PBM-induced changes in HS accumulation, astrocyte activation, CD206 (an anti-inflammatory marker) and BDNF expression in the brains of Sanfilippo mice, there was a near-normalisation of microglial activation in older MPS IIIA mice by 904 nm PBM, with decreased IBA1 expression and a return of their morphology towards a resting state. Immune cell immunophenotyping of peripheral blood with mass cytometry revealed increased pro-inflammatory signalling through pSTAT1 and p-p38 in NK and T cells in young but not older MPS IIIA mice (5 weeks of age), and expansion of NK, B and CD8+ T cells in older affected mice (17 weeks of age), highlighting the importance of innate and adaptive lymphocytes in Sanfilippo syndrome. Notably, 670 and 904 nm PBM both reversed the Sanfilippo-induced increase in pSTAT1 and p-p38 expression in multiple leukocyte populations in young mice, while 904 nm reversed the increase in NK cells in older mice. In conclusion, this is the first study to demonstrate the beneficial effects of PBM in Sanfilippo mice. The distinct reduction in microglial activation and NK cell pro-inflammatory signalling and number suggests PBM may alleviate neuroinflammation and lymphocyte activation, encouraging further investigation of PBM as a standalone, or complementary therapy in Sanfilippo syndrome.

Long-term efficacy and safety of baricitinib in patients with severe alopecia areata: 104-week results from BRAVE-AA1 and BRAVE-AA2.

BACKGROUND: Efficacy of the Janus kinase (JAK) inhibitor baricitinib for severe alopecia areata (AA) continuously increased over 52 weeks in two Phase 3 trials. There are limited long-term data on JAK inhibitors in AA. OBJECTIVES: To evaluate efficacy and safety of baricitinib for severe AA through 104 weeks of continuous therapy. METHODS: Integrated data from the BRAVE-AA1 and BRAVE-AA2 Phase 3 trials included adults with Severity of Alopecia Tool (SALT) scores ≥50 (≥50% scalp hair loss) randomized to and continuously treated with 2-mg or 4-mg baricitinib through Week 104. Patients who qualified to remain on continuous treatment included subjects who achieved SALT score ≤20 at Week 52 (Week-52 responders; 2-mg: N = 65; 4-mg: N = 129) and baricitinib 4-mg-treated patients who had SALT score >20 at Week 52 but achieved SALT score ≤20 at prior visit(s) and/or had significant improvement in eyebrow or eyelash hair growth relative to baseline by Week 52 (Week-52 mixed responders; N = 110). Week-104 outcomes included the proportion of patients achieving SALT score ≤20 (≤20% scalp hair loss). Data were censored after treatment discontinuation. RESULTS: Among baricitinib 4-mg-treated and baricitinib 2-mg-treated Week-52 responders, 90.7% and 89.2%, respectively, maintained SALT score ≤20 at Week 104. Among Week-52 mixed responders, 39.1% reached SALT score ≤20 by Week 104. Continued improvement in eyebrow and eyelash regrowth was observed across groups. The most frequent treatment-emergent adverse events were COVID-19, upper respiratory tract infection, headache, nasopharyngitis, acne, urinary tract infection and creatine phosphokinase increase. CONCLUSIONS: Baricitinib demonstrated a high level of maintenance of efficacy over 104 weeks in patients with severe AA. Efficacy increased in Week-52 mixed responders, illustrating that long-term treatment is necessary to observe maximum benefit in some patients. No new safety signals were observed.

Large language models and agricultural extension services.

Several factors have traditionally hampered the effectiveness of agricultural extension services, including limited institutional capacity and reach. Here we assess the potential of large language models (LLMs), specifically Generative Pre-trained Transformer (GPT), to transform agricultural extension. We focus on the ability of LLMs to simplify scientific knowledge and provide personalized, location-specific and data-driven agricultural recommendations. We emphasize shortcomings of this technology, informed by real-life testing of GPT to generate technical advice for Nigerian cassava farmers. To ensure a safe and responsible dissemination of LLM functionality across farming worldwide, we propose an idealized LLM design process with human experts in the loop.

Forecasting emergent risks in advanced AI systems: an analysis of a future road transport management system.

Artificial Intelligence (AI) is being increasingly implemented within road transport systems worldwide. Next generation of AI, Artificial General Intelligence (AGI) is imminent, and is anticipated to be more powerful than current AI. AGI systems will have a broad range of abilities and be able to perform multiple cognitive tasks akin to humans that will likely produce many expected benefits, but also potential risks. This study applied the EAST Broken Links approach to forecast the functioning of an AGI system tasked with managing a road transport system and identify potential risks. In total, 363 risks were identified that could have adverse impacts on the stated goals of safety, efficiency, environmental sustainability, and economic performance of the road system. Further, risks beyond the stated goals were identified; removal from human control, mismanaging public relations, and self-preservation. A diverse set of systemic controls will be required when designing, implementing, and operating future advanced technologies.Practitioner summary: This study demonstrated the utility of HFE methods for formally considering risks associated with the design, implementation, and operation of future technologies. This study has implications for AGI research, design, and development to ensure safe and ethical AGI implementation.

Gustation in insects: taste qualities and types of evidence used to show taste function of specific body parts.

The insect equivalent of taste buds are gustatory sensilla, which have been found on mouthparts, pharynxes, antennae, legs, wings, and ovipositors. Most gustatory sensilla are uniporous, but not all apparently uniporous sensilla are gustatory. Among sensilla containing more than one neuron, a tubular body on one dendrite is also indicative of a taste sensillum, with the tubular body adding tactile function. But not all taste sensilla are also tactile. Additional morphological criteria are often used to recognize if a sensillum is gustatory. Further confirmation of such criteria by electrophysiological or behavioral evidence is needed. The five canonical taste qualities to which insects respond are sweet, bitter, sour, salty, and umami. But not all tastants that insects respond to easily fit in these taste qualities. Categories of insect tastants can be based not only on human taste perception, but also on whether the response is deterrent or appetitive and on chemical structure. Other compounds that at least some insects taste include, but are not limited to: water, fatty acids, metals, carbonation, RNA, ATP, pungent tastes as in horseradish, bacterial lipopolysaccharides, and contact pheromones. We propose that, for insects, taste be defined not only as a response to nonvolatiles but also be restricted to responses that are, or are thought to be, mediated by a sensillum. This restriction is useful because some of the receptor proteins in gustatory sensilla are also found elsewhere.

Interactions between the aging brain and motor task complexity across the lifespan: balancing brain activity resource demand and supply.

The Compensation Related Utilization of Neural Circuits Hypothesis (CRUNCH) proposes a framework for understanding task-related brain activity changes as a function of healthy aging and task complexity. Specifically, it affords the following predictions: (i) all adult age groups display more brain activation with increases in task complexity, (ii) older adults show more brain activation compared with younger adults at low task complexity levels, and (iii) disproportionately increase brain activation with increased task complexity, but (iv) show smaller (or no) increases in brain activation at the highest complexity levels. To test these hypotheses, performance on a bimanual tracking task at 4 complexity levels and associated brain activation were assessed in 3 age groups (20-40, 40-60, and 60-80 years, n = 99). All age groups showed decreased tracking accuracy and increased brain activation with increased task complexity, with larger performance decrements and activation increases in the older age groups. Older adults exhibited increased brain activation at a lower complexity level, but not the predicted failure to further increase brain activity at the highest complexity level. We conclude that older adults show more brain activation than younger adults and preserve the capacity to deploy increased neural resources as a function of task demand.

A Rare Case of Severe Burn Injury to the Oropharynx Caused by a Flare Gun.

Flare gun injuries are rare, and patients often present with complex trauma that may require multiple operative interventions. Our objective is to explore a case of a 15-year-old male, who presented with second-degree flame burns to the face, left upper extremity and bilateral hands, as well as third-degree burns to the oropharynx and a tongue laceration after a flare gun was discharged into his mouth. The patient underwent multiple debridements of the oral cavity and oropharynx, and his hospital course was complicated by an intra-oral abscess. He eventually made a full recovery and was discharged. This case not only illustrates the need for early operative intervention, but it also underscores the need for awareness campaigns that highlight the dangers of flare guns and similar devices.

Les blessures par pistolet lance-fusée sont rares. Les patients souffrent fréquemment de blessures complexes nécessitant de multiples interventions. Nous présentons le cas d'un adolescent de 15 ans se présentant avec des brûlures par flamme de la face, du membre supérieur gauche et des 2 mains (2ème degré) ainsi qu'une atteinte au 3ème de degré de l'oropharynx et une lacération de langue, consécutivement à la mise à feu intrabuccale d'un pistolet lance-fusée. Il a nécessité de multiples débridements des atteintes buccale et pharyngée, l'évolution ayant été compliquée par plusieurs abcès. Il est finalement sorti guéri. Cette observation illustre d'une part la nécessité d'une prise en chirurgicale précoce. Elle souligne la nécessité de campagnes d'information sur la dangerosité des pistolets lance-fusée et matériels similaires.

medna-metadata: an open-source data management system for tracking environmental DNA samples and metadata.

MOTIVATION: Environmental DNA (eDNA), as a rapidly expanding research field, stands to benefit from shared resources including sampling protocols, study designs, discovered sequences, and taxonomic assignments to sequences. High-quality community shareable eDNA resources rely heavily on comprehensive metadata documentation that captures the complex workflows covering field sampling, molecular biology lab work, and bioinformatic analyses. There are limited sources that provide documentation of database development on comprehensive metadata for eDNA and these workflows and no open-source software. RESULTS: We present medna-metadata, an open-source, modular system that aligns with Findable, Accessible, Interoperable, and Reusable guiding principles that support scholarly data reuse and the database and application development of a standardized metadata collection structure that encapsulates critical aspects of field data collection, wet lab processing, and bioinformatic analysis. Medna-metadata is showcased with metabarcoding data from the Gulf of Maine (Polinski et al., 2019). AVAILABILITY AND IMPLEMENTATION: The source code of the medna-metadata web application is hosted on GitHub (https://github.com/Maine-eDNA/medna-metadata). Medna-metadata is a docker-compose installable package. Documentation can be found at https://medna-metadata.readthedocs.io/en/latest/?badge=latest. The application is implemented in Python, PostgreSQL and PostGIS, RabbitMQ, and NGINX, with all major browsers supported. A demo can be found at https://demo.metadata.maine-edna.org/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Investigating dilution ventilation control strategies in a modern U.S. school bus in the context of the COVID-19 pandemic.

Fresh air ventilation has been identified as a widely accepted engineering control effective at diluting air contaminants in enclosed environments. The goal of this study was to evaluate the effects of selected ventilation measures on air change rates in school buses. Air changes per hour (ACH) of outside air were measured using a well-established carbon dioxide (CO2) tracer gas decay method. Ventilation was assessed while stationary and while traversing standardized route during late autumn/winter months in Colorado. Seven CO2 sensors located at the driver's seat and at passenger seats in the front, middle, and rear of the bus yielded similar and consistent measurements. Buses exhibited little air exchange in the absence of ventilation (ACH = 0.13 when stationary; ACH = 1.85 when mobile). Operating the windshield defroster to introduce fresh outside air increased ACH by approximately 0.5-1 ACH during mobile and stationary phases. During the mobile phase (average speed of 23 miles per hour (mph)), the combination of the defroster and two open ceiling hatches (with a powered fan on the rear hatch) yielded an ACH of approximately 9.3 ACH. A mobile phase ACH of 12.4 was achieved by the combination of the defroster, ceiling hatches, and six passenger windows open 2 inches in the middle area of the bus. A maximum mobile phase ACH of 22.1 was observed by using the defroster, open ceiling hatches, driver window open 4 inches, and every other passenger window open 2 inches. For reference, ACHs recommended in patient care settings where patients are being treated for airborne infectious diseases range from 6 to ≥12 ACHs. The results indicate that practical ventilation protocols on school buses can achieve air change rates thought to be capable of reducing airborne viral transmission to the bus driver and student passengers during the COVID-19 pandemic.

Network-specific differences in transient brain activity at rest are associated with age-related reductions in motor performance.

Multiple functional changes occur in the brain with increasing age. Among those, older adults typically display more restricted fluctuations of brain activity, both during resting-state and task execution. These altered dynamic patterns have been linked to reduced task performance across multiple behavioral domains. Windowed functional connectivity, which is typically employed in the study of connectivity dynamics, however, might not be able to properly characterize moment-to-moment variations of individual networks. In the present study, we used innovation-driven co-activation patterns (ICAP) to overcome this limitation and investigate the length (duration) and frequency (innovation) in which various brain networks emerged across the adult lifespan (N= 92) during a resting-state period. We identified a link between increasing age and a tendency to engage brain areas with distinct functional associations simultaneously as a single network. The emergence of isolated and spatially well-defined visual, motor, frontoparietal, and posterior networks decreased with increased age. This reduction in dynamics of specialized networks mediated age-related performance decreases (i.e., increases in interlimb interference) in a bimanual motor task. Altogether, our findings demonstrated that older compared to younger adults tend to activate fewer network configurations, which include multiple functionally distinct brain areas. The reduction in independent emergence of functionally well-defined and task-relevant networks may reflect an expression of brain dedifferentiation and is likely associated with functional modulatory deficits, negatively impacting motor behavior.

Diet and Nutrition of Adult Spalangia cameroni (Hymenoptera: Pteromalidae), a Parasitoid of Filth Flies.

Most parasitoid wasps parasitize herbivorous insects, so nectar from flowers is readily available. However, parasitoid wasps are also an important component of the rich invertebrate communities at livestock facilities in large accumulations of manure, where flowers are largely absent. Little is known about adult parasitoid diet and nutrition in these communities. The present study examined this in Spalangia cameroni Perkins, a pupal parasitoid of filth flies. Like many parasitoid wasps, S. cameroni feed on host fluids, and in the laboratory readily feed on honey or a sucrose solution, which increases their longevity. Here adult longevity in the presence of six potential food sources, bovine manure, sorghum silage, bovine milk, buckwheat inflorescence (Polygonaceae), sweet alyssum inflorescence (Brassicaceae), or dandelion inflorescence (Asteraceae), was compared to that with water or honey. Only parasitoids given buckwheat lived as long as parasitoids given honey, and parasitoids given honey or buckwheat lived longer than parasitoids given water. Parasitoids readily ate buckwheat nectar, avoiding pollen grains. Diet affected the amount of free sugars, glycogen, and lipids in complex ways. Compared to parasitoids that were given just water, parasitoids with access to honey or sucrose had higher sugar and glycogen levels, but not detectably higher lipid levels. Access to buckwheat had no detectable effect on a parasitoid's free sugar, glycogen, or lipid levels; however, then after 4 d with just water, sugar levels were lower and glycogen levels were higher compared to parasitoids that had been given access to only water the entire time.

Classical Resummation and Breakdown of Strong-Field QED.

QED perturbation theory has been conjectured to break down in sufficiently strong backgrounds, obstructing the analysis of strong-field physics. We show that the breakdown occurs even in classical electrodynamics, at lower field strengths than previously considered, and that it may be cured by resummation. As a consequence, an analogous resummation is required in QED. A detailed investigation shows, for a range of observables, that unitarity removes diagrams previously believed to be responsible for the breakdown of QED perturbation theory.

Complement in metabolic disease: metaflammation and a two-edged sword.

We are currently experiencing an enduring global epidemic of obesity and diabetes. It is now understood that chronic low-grade tissue inflammation plays an important role in metabolic disease, brought upon by increased uptake of a so-called Western diet, and a more sedentary lifestyle. Many evolutionarily conserved links exist between metabolism and the immune system, and an imbalance in this system induced by chronic over-nutrition has been termed 'metaflammation'. The complement system is an important and evolutionarily ancient part of innate immunity, but recent work has revealed that complement not only is involved in the recognition of pathogens and induction of inflammation, but also plays important roles in cellular and tissue homeostasis. Complement can therefore contribute both positively and negatively to metabolic control, depending on the nature and anatomical site of its activity. This review will therefore focus on the interactions of complement with mechanisms and tissues relevant for metabolic control, obesity and diabetes.

Economic analysis of prenatal fetoscopic vs open-hysterotomy repair of open neural tube defect.

OBJECTIVE: Fetal repair of an open neural tube defect (ONTD) by open hysterotomy has been shown to reduce the need for ventriculoperitoneal shunting and improve motor outcomes for infants, but increases the risk of Cesarean section and prematurity. Fetoscopic repair is an alternative approach that may confer similar neurological benefits but allows for vaginal delivery and reduces the incidence of hysterotomy-related complications. We sought to compare the costs of care from fetal surgery until neonatal discharge, as well as the clinical outcomes, associated with each surgical approach. METHODS: This was a retrospective cohort study of patients who underwent prenatal ONTD repair, using either the open-hysterotomy or the fetoscopic approach, at a single institution between 2012 and 2018. Clinical outcomes were collected by chart review. A cost-consequence analysis was conducted from the hospital perspective, and included all inpatient and ambulatory hospital and physician costs incurred for the care of mothers and their infants, from the time of maternal admission for fetal ONTD repair up to postnatal maternal and infant discharge. Costs were estimated using cost-to-charge ratios for hospital billing and the Medicare physician fee schedule for physician billing. RESULTS: Seventy-eight patients were included in the analysis, of whom 47 underwent fetoscopic repair and 31 underwent open-hysterotomy repair. In the fetoscopic-repair group, compared with the open-repair group, fewer women underwent Cesarean section (53% vs 100%; P < 0.001) and the median gestational age at birth was significantly higher (38.1 weeks (interquartile range (IQR), 35.2-39.1 weeks) vs 35.7 weeks (IQR, 33.9-37.0 weeks); P < 0.001). No case of uterine dehiscence was observed in the fetoscopic-repair group, compared with an incidence of 16% in the open-repair group. After adjusting for baseline characteristics, there was no significant difference in the total cost of care between the fetoscopic-repair and the open-repair groups (median, $76 978 (IQR, $60 312-$115 386) vs $65 103 (IQR, $57 758-$108 103); P = 0.458). CONCLUSIONS: Fetoscopic repair of ONTD, when compared with the open-hysterotomy approach, reduces the incidence of Cesarean section and preterm delivery with no significant difference in total costs of care from surgery to infant discharge. This novel approach may represent a cost-effective alternative to improve maternal and neonatal outcomes for this high-risk population. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

Increased paediatric presentations of severe diabetic ketoacidosis in an Australian tertiary centre during the COVID-19 pandemic.

AIMS: To determine if the frequency of severe diabetic ketoacidosis at presentation of new-onset type 1 diabetes to an Australian tertiary centre increased during the initial period of restrictions resulting from the COVID-19 pandemic (March to May 2020). METHODS: Data were collected on presentations of newly diagnosed type 1 diabetes as well as on all paediatric presentations to the emergency department of a tertiary centre between 2015 and 2020. Data from the period of initial COVID restrictions in Australia (March to May 2020) were compared to the period March to May of the previous 5 years (pre-pandemic periods). RESULTS: The number of new diagnoses of type 1 diabetes was comparable in the pandemic period and pre-pandemic periods (11 in 2020 vs range 6-10 in 2015-2019). The frequency of severe diabetic ketoacidosis was significantly higher in the pandemic period compared to the pre-pandemic periods (45% vs 5%; P <0.003), odds ratio 16.7 (95% CI 2.0, 194.7). The overall frequency of diabetic ketoacidosis was also significantly higher during the pandemic period (73% vs 26%; P <0.007), odds ratio 7.5 (95% CI 1.7, 33.5). None of the individuals tested positive for COVID-19. Presentations of people aged <18 years to the emergency department decreased by 27% in the pandemic period compared to the average of the pre-pandemic periods (4799 vs 6550; range 6268 to 7131). CONCLUSIONS: A significant increase in the frequency of severe diabetic ketoacidosis at presentation of type 1 diabetes was observed during the initial period of COVID-19 restrictions. We hypothesize that concern about presenting to hospital during a pandemic led to a delay in diagnosis. These data have important implications for advocacy of seeking healthcare for non-pandemic-related conditions during a global pandemic.

Stress Modulates the Balance between Hippocampal and Motor Networks during Motor Memory Processing.

The functional interaction between hippocampo- and striato-cortical regions during motor sequence learning is essential to trigger optimal memory consolidation. Based on previous evidence from other memory domains that stress alters the balance between these systems, we investigated whether exposure to stress prior to motor learning modulates motor memory processes. Seventy-two healthy young individuals were exposed to a stressful or nonstressful control intervention prior to training on a motor sequence learning task in a magnetic resonance imaging (MRI) scanner. Consolidation was assessed with an MRI retest after a sleep episode. Behavioral results indicate that stress prior to learning did not influence motor performance. At the neural level, stress induced both a larger recruitment of sensorimotor regions and a greater disengagement of hippocampo-cortical networks during training. Brain-behavior regression analyses showed that while this stress-induced shift from (hippocampo-)fronto-parietal to motor networks was beneficial for initial performance, it was detrimental for consolidation. Our results provide the first experimental evidence that stress modulates the neural networks recruited during motor memory processing and therefore effectively unify concepts and mechanisms from diverse memory fields. Critically, our findings suggest that intersubject variability in brain responses to stress determines the impact of stress on motor learning and subsequent consolidation.

Toxicity of fluralaner, a companion animal insecticide, relative to industry-leading agricultural insecticides against resistant and susceptible strains of filth flies.

Filth flies cause billions of dollars of losses annually to the animal production industry. Fluralaner is a relatively new pesticide currently sold for control of fleas, ticks, and mites on companion animals and poultry. We examined the efficacy of fluralaner against three species of filth flies. Insecticide-susceptible horn flies and stable flies were tested topically. Fluralaner outperformed permethrin by > 2-fold for the horn flies but underperformed permethrin by > 45-fold for stable flies at 24 h. House flies were tested topically with fluralaner in comparison to permethrin at 48 h and orally with fluralaner in comparison to imidacloprid at 24 h. Topical fluralaner was 6- to 28-fold as toxic as permethrin in four pyrethroid-resistant strains and not significantly less toxic than permethrin in a susceptible strain and a mildly pyrethroid-resistant strain. There was slight cross-resistance between topically applied fluralaner and permethrin in all five insecticide-resistant strains tested. Oral fluralaner was more toxic than imidacloprid in all four house fly strains tested, 9- to 118-fold as toxic. Oral cross-resistance between imidacloprid and fluralaner was not detected, but imidacloprid resistance was not high in any of the tested strains. Fluralaner shows promise for control of horn flies and house flies.

A Field-Relevant Concentration of the Insecticide Imidacloprid Affects Grooming, Locomotion, and Longevity in the Biological Control Agent Spalangia endius (Hymenoptera: Pteromalidae).

Foreign materials like insecticides may increase grooming in insects; and generally, grooming may be expected to reduce effects of insecticides, but this may not be the case when grooming involves the mouth and hence a risk of ingestion. To examine this, female Spalangia endius, a wasp that parasitizes filth fly pupae, were exposed to a surface coated with a low concentration of imidacloprid or not. Their mouthparts were sealed or not to determine whether sealing is a useful method for examining effects of mouth grooming. Wasps mouth-groomed more frequently while exposed to imidacloprid than when not. However, imidacloprid did not increase the number of times that a wasp groomed the rest of her body, and this was true regardless of whether or not her mouthparts were sealed. While exposed to imidacloprid, wasps spent less time locomoting only if their mouthparts were not sealed. Having been exposed to imidacloprid also decreased subsequent longevity, from 9 to 7 d. These effects of imidacloprid on grooming, locomotion, and longevity occurred despite exposure being for just 5 min and to only 2% of the amount that will be present in an area immediately after house fly baits are scattered at their recommended coverage. This is such a low amount that, with 48 h of constant exposure, mortality of these wasps is only 10%. Having mouthparts sealed decreased locomotion and longevity regardless of exposure to imidacloprid. Thus, sealing mouthparts is not useful for measuring effects of mouth grooming.

High-protein meals require 30% additional insulin to prevent delayed postprandial hyperglycaemia.

AIM: To determine the amount of additional insulin required for a high-protein meal to prevent postprandial hyperglycaemia in individuals with type 1 diabetes using insulin pump therapy. METHODS: In this randomized cross-over study, 26 participants aged 8-40 years, HbA1c < 65 mmol/mol (8.1%), received a 50 g protein, 30 g carbohydrate, low-fat (< 1 g) breakfast drink over five consecutive days at home. A standard insulin dose (100%) was compared with additional doses of 115, 130, 145 and 160% for the protein, in randomized order. Doses were commenced 15-min pre-drink and delivered over 3 h using a combination bolus with 65% of the standard dose given up front. Postprandial glycaemia was assessed by 4 h of continuous glucose monitoring. RESULTS: The 100% dosing resulted in postprandial hyperglycaemia. From 120 min, ≥ 130% doses resulted in significantly lower postprandial glycaemic excursions compared with 100% (P < 0.05). A 130% dose produced a mean (sd) glycaemic excursion that was 4.69 (2.42) mmol/l lower than control, returning to baseline by 4 h (P < 0.001). From 120 min, there was a significant increase in the risk of hypoglycaemia compared with control for 145% [odds ratio (OR) 25.4, 95% confidence interval (CI) 5.5-206; P < 0.001) and 160% (OR 103, 95% CI 19.2-993; P < 0.001). Some 81% (n = 21) of participants experienced hypoglycaemia following a 160% dose, whereas 58% (n = 15) experienced hypoglycaemia following a 145% dose. There were no hypoglycaemic events reported with 130%. CONCLUSIONS: The addition of 30% more insulin to a standard dose for a high-protein meal, delivered using a combination bolus, improves postprandial glycaemia without increasing the risk of hypoglycaemia.