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Cancer is a significant global socioeconomic burden, as millions of new cases and deaths occur annually. In 2020, almost 10 million cancer deaths were recorded worldwide. Advancements in cancer gene therapy have revolutionized the landscape of cancer treatment. An approach with promising potential for cancer gene therapy is introducing genes to cancer cells that encode for chemotherapy prodrug metabolizing enzymes, such as Cytochrome P450 (CYP) enzymes, which can contribute to the effective elimination of cancer cells. This can be achieved through gene-directed enzyme prodrug therapy (GDEPT). CYP enzymes can be genetically engineered to improve anticancer prodrug conversion to its active metabolites and to minimize chemotherapy side effects by reducing the prodrug dosage. Rational design, directed evolution, and phylogenetic methods are some approaches to developing tailored CYP enzymes for cancer therapy. Here, we provide a compilation of genetic modifications performed on CYP enzymes aiming to build highly efficient therapeutic genes capable of bio-activating different chemotherapeutic prodrugs. Additionally, this review summarizes promising preclinical and clinical trials highlighting engineered CYP enzymes’ potential in GDEPT. Finally, the challenges, limitations, and future directions of using CYP enzymes for GDEPT in cancer gene therapy are discussed.

Abstract Stings of certain ant species (Hymenoptera: Formicidae) can cause intense, long-lasting nociception. Here we show that the major contributors to these symptoms are venom peptides that modulate the activity of voltage-gated sodium (NaV) channels, reducing their voltage threshold for activation and inhibiting channel inactivation. These peptide toxins are likely vertebrate-selective, consistent with a primarily defensive function. They emerged early in the Formicidae lineage and may have been a pivotal factor in the expansion of ants.

Abstract Background Spirometric small airways obstruction (SAO) is common in the general population. Whether spirometric SAO is associated with respiratory symptoms, cardiometabolic diseases, and quality of life (QoL) is unknown. Methods Using data from the Burden of Obstructive Lung Disease study (N = 21,594), we defined spirometric SAO as the mean forced expiratory flow rate between 25 and 75% of the FVC (FEF25-75) less than the lower limit of normal (LLN) or the forced expiratory volume in 3 s to FVC ratio (FEV3/FVC) less than the LLN. We analysed data on respiratory symptoms, cardiometabolic diseases, and QoL collected using standardised questionnaires. We assessed the associations with spirometric SAO using multivariable regression models, and pooled site estimates using random effects meta-analysis. We conducted identical analyses for isolated spirometric SAO (i.e. with FEV1/FVC ≥ LLN). Results Almost a fifth of the participants had spirometric SAO (19% for FEF25-75; 17% for FEV3/FVC). Using FEF25-75, spirometric SAO was associated with dyspnoea (OR = 2.16, 95% CI 1.77–2.70), chronic cough (OR = 2.56, 95% CI 2.08–3.15), chronic phlegm (OR = 2.29, 95% CI 1.77–4.05), wheeze (OR = 2.87, 95% CI 2.50–3.40) and cardiovascular disease (OR = 1.30, 95% CI 1.11–1.52), but not hypertension or diabetes. Spirometric SAO was associated with worse physical and mental QoL. These associations were similar for FEV3/FVC. Isolated spirometric SAO (10% for FEF25-75; 6% for FEV3/FVC), was also associated with respiratory symptoms and cardiovascular disease. Conclusion Spirometric SAO is associated with respiratory symptoms, cardiovascular disease, and QoL. Consideration should be given to the measurement of FEF25-75 and FEV3/FVC, in addition to traditional spirometry parameters.

Abstract Background Eusociality is widely considered to evolve through kin selection, where the reproductive success of an individual’s close relative is favored at the expense of its own. High genetic relatedness is thus considered a prerequisite for eusociality. While ants are textbook examples of eusocial animals, not all ants form colonies of closely related individuals. One such example is the ectatommine ant Rhytidoponera metallica, which predominantly forms queen-less colonies that have such a low intra-colony relatedness that they have been proposed to represent a transient, unstable form of eusociality. However, R. metallica is among the most abundant and widespread ants on the Australian continent. This apparent contradiction provides an example of how inclusive fitness may not by itself explain the maintenance of eusociality and raises the question of what other selective advantages maintain the eusocial lifestyle of this species. Results We provide a comprehensive portrait of the venom of R. metallica and show that the colony-wide venom consists of an exceptionally high diversity of functionally distinct toxins for an ant. These toxins have evolved under strong positive selection, which is normally expected to reduce genetic variance. Yet, R. metallica exhibits remarkable intra-colony variation, with workers sharing only a relatively small proportion of toxins in their venoms. This variation is not due to the presence of chemical castes, but has a genetic foundation that is at least in part explained by toxin allelic diversity. Conclusions Taken together, our results suggest that the toxin diversity contained in R. metallica colonies may be maintained by a form of group selection that selects for colonies that can exploit more resources and defend against a wider range of predators. We propose that increased intra-colony genetic variance resulting from low kinship may itself provide a selective advantage in the form of an expanded pharmacological venom repertoire. These findings provide an example of how group selection on adaptive phenotypes may contribute to maintaining eusociality where a prerequisite for kin selection is diminished.

Voltage-gated Ca2+ channel subtype Cav2.3 represents a potential drug target for neurological diseases. Here, authors report cryo-EM structures of Cav2.3 and its mutant to reveal the crosstalk of intracellular segments, which may facilitate future drug discovery.

The rise of antimicrobial resistance caused by inappropriate use of these agents in various settings has become a global health threat. Nanotechnology offers the potential for the synthesis of nanoparticles (NPs) with antimicrobial activity, such as iron oxide nanoparticles (IONPs). The use of IONPs is a promising way to overcome antimicrobial resistance or pathogenicity because of their ability to interact with several biological molecules and to inhibit microbial growth. In this review, we outline the pivotal findings over the past decade concerning methods for the green synthesis of IONPs using bacteria, fungi, plants, and organic waste. Subsequently, we delve into the primary challenges encountered in green synthesis utilizing diverse organisms and organic materials. Furthermore, we compile the most common methods employed for the characterization of these IONPs. To conclude, we highlight the applications of these IONPs as promising antibacterial, antifungal, antiparasitic, and antiviral agents.

Abstract In the pregnant mother and her fetus, chronic prenatal stress results in entrainment of the fetal heartbeat by the maternal heartbeat, quantified by the fetal stress index (FSI). Deep learning (DL) is capable of pattern detection in complex medical data with high accuracy in noisy real-life environments, but little is known about DL’s utility in non-invasive biometric monitoring during pregnancy. A recently established self-supervised learning (SSL) approach to DL provides emotional recognition from electrocardiogram (ECG). We hypothesized that SSL will identify chronically stressed mother-fetus dyads from the raw maternal abdominal electrocardiograms (aECG), containing fetal and maternal ECG. Chronically stressed mothers and controls matched at enrolment at 32 weeks of gestation were studied. We validated the chronic stress exposure by psychological inventory, maternal hair cortisol and FSI. We tested two variants of SSL architecture, one trained on the generic ECG features for emotional recognition obtained from public datasets and another transfer-learned on a subset of our data. Our DL models accurately detect the chronic stress exposure group (AUROC = 0.982 ± 0.002), the individual psychological stress score (R2 = 0.943 ± 0.009) and FSI at 34 weeks of gestation (R2 = 0.946 ± 0.013), as well as the maternal hair cortisol at birth reflecting chronic stress exposure (0.931 ± 0.006). The best performance was achieved with the DL model trained on the public dataset and using maternal ECG alone. The present DL approach provides a novel source of physiological insights into complex multi-modal relationships between different regulatory systems exposed to chronic stress. The final DL model can be deployed in low-cost regular ECG biosensors as a simple, ubiquitous early stress detection and monitoring tool during pregnancy. This discovery should enable early behavioral interventions.

Abstract Background To compare clinical intra and early postoperative outcomes between conventional Holmium laser enucleation of the prostate (HoLEP) and Holmium laser enucleation of the prostate using the Virtual Basket tool (VB-HoLEP) to treat benign prostatic hyperplasia (BPH). Methods This prospective randomized study enrolled consecutive patients with BPH, who were assigned to undergo either HoLEP (n = 100), or VB-HoLEP (n = 100). All patients were evaluated preoperatively and postoperatively, with particular attention to catheterization time, operative time, blood loss, irrigation volume and hospital stay. We also evaluated the patients at 3 and 6 months after surgery and assessed maximum flow rate (Qmax), postvoid residual urine volume (PVR), the International Prostate Symptom Score (IPSS) and the Quality of Life score (QOLS). Results No significant differences in preoperative parameters between patients in each study arm were found. Compared to HoLEP, VB-HoLEP resulted in less hemoglobin decrease (2.54 vs. 1.12 g/dl, P = 0.03) and reduced operative time (57.33 ± 29.71 vs. 42.99 ± 18.51 min, P = 0.04). HoLEP and VB-HoLEP detrmined similar catheterization time (2.2 vs. 1.9 days, P = 0.45), irrigation volume (33.3 vs. 31.7 l, P = 0.69), and hospital stay (2.8 vs. 2.7 days, P = 0.21). During the 6-month follow-up no significant differences in IPSS, Qmax, PVR, and QOLS were demonstrated. Conclusions HoLEP and VB-HoLEP are both efficient and safe procedures for relieving lower urinary tract symptoms. VB-HoLEP was statistically superior to HoLEP in blood loss and operative time. However, procedures did not differ significantly in catheterization time, hospital stay, and irrigation volume. No significant differences were demonstrated in QOLS, IPSS, Qmax and PVR throughout the 6-month follow-up. Trial Registration: Current Controlled Trials ISRCTN72879639; date of registration: June 25th, 2015. Retrospectively registred.

We have created tools that automate one of the most burdensome aspects of documenting the provenance of research data: describing data transformations performed by statistical software. Researchers in many fields use statistical software (SPSS, Stata, SAS, R, Python) for data transformation and data management as well as analysis. The C2Metadata ("Continuous Capture of Metadata for Statistical Data") Project creates a metadata workflow paralleling the data management process by deriving provenance information from scripts used to manage and transform data. C2Metadata differs from most previous data provenance initiatives by documenting transformations at the variable level rather than describing a sequence of opaque programs. Command scripts for statistical software are translated into an independent Structured Data Transformation Language (SDTL), which serves as an intermediate language for describing data transformations. SDTL can be used to add variable-level provenance to data catalogues and codebooks and to create "variable lineages" for auditing software operations. Better data documentation makes research more transparent and expands the discovery and re-use of research data.

Abstract Background Intense exercise is a systemic stressor associated with the release of “danger” molecules – alarmins, by damaged or dying cells into systemic circulation to evoke a sterile inflammatory response. Compared with research in clinical diseases, physiological responses of alarmins to exercise and training are not well studied. Short-term responses to exercise and training using a panel of alarmins – HMGB1, S100A8/A9, HSP70 and sRAGE may reveal unique aspects of stress responses to strenuous exercise, with important ramifications when prescribing exercise to generally healthy adults. Methods A 3-week, high-intensity training program was performed by healthy young men (N = 7). Concurrent aerobic and resistance exercises were performed on 3 consecutive days each week. Blood and saliva were collected before (Pre), immediately after (Post), and 30 min (30 min) after exercise each week, and 24 h after the final exercise session in week 3 (24 h). Results Plasma HMGB1, S100A8/A9 and HSP70 increased from Pre to Post (P

Purpose To develop and characterize a tissue-mimicking phantom that enables the direct comparison of magnetic resonance (MR) and ultrasound (US) imaging techniques useful for monitoring high-intensity focused ultrasound (HIFU) treatments. With no additions, gelatin phantoms produce little if any scattering required for US imaging. This study characterizes the MR and US image characteristics as a function of psyllium husk concentration, which was added to increase US scattering. Methods Gelatin phantoms were constructed with varying concentrations of psyllium husk. The effects of psyllium husk concentration on US B-mode and MR imaging were evaluated at nine different concentrations. T1, T2, and T2* MR maps were acquired. Acoustic properties (attenuation and speed of sound) were measured at frequencies of 0.6, 1.0, 1.8, and 3.0 MHz using a through-transmission technique. Phantom elastic properties were evaluated for both time and temperature dependence. Results Ultrasound image echogenicity increased with increasing psyllium husk concentration while quality of gradient-recalled echo MR images decreased with increasing concentration. For all phantoms, the measured speed of sound ranged between 1567–1569 m/s and the attenuation ranged between 0.42–0.44 dB/(cm·MHz). Measured T1 ranged from 974–1051 ms. The T2 and T2* values ranged from 97–108 ms and 48–88 ms, respectively, with both showing a decreasing trend with increased psyllium husk concentration. Phantom stiffness, measured using US shear-wave speed measurements, increased with age and decreased with increasing temperature. Conclusions The presented dual-use tissue-mimicking phantom is easy to manufacture and can be used to compare and evaluate US-guided and MR-guided HIFU imaging protocols.

The paper reviews the impact that COVID-19 has had on the ambitions of countries to meet the Paris Accord of reducing emissions to keep global temperature increases to below 2 ºC in this century. It notes that as nations recover from the crises, if no additional measures are taken, emissions of greenhouse gases will rise again and return to their old pathway as they did after previous crises. The paper proposes actions in the short and medium terms to build back differently this time and help meet the global climate challenge.

Abstract An individualization of exercise prescription is implemented mainly in terms of intensity but not for duration. To survey the need for an individualized exercise duration prescription, we investigated acute physiologic responses during constant‐load exercise of maximal duration (tmax) and determined so‐called duration thresholds. Differences between absolute (min) and relative terms (% tmax) of exercise duration were analyzed. Healthy young and trained male and female participants (n = 11) performed an incremental exercise test and one tmax constant‐load exercise test at a target intensity of 10% of maximal power output below the second lactate turn point (LTP2). Blood lactate, heart rate, and spirometric data were measured during all tests. tmax was markedly different across subjects (69.6 ± 14.8 min; range: 40–90 min). However, distinct duration phases separated by duration thresholds (DTh) were found in most measured variables. These duration thresholds (except DTh1) were significantly related to tmax (DTh2: r2 = 0.90, p

Flare frequency distributions represent a key approach to addressing one of the largest problems in solar and stellar physics: determining the mechanism that counterintuitively heats coronae to temperatures that are orders of magnitude hotter than the corresponding photospheres. It is widely accepted that the magnetic field is responsible for the heating, but there are two competing mechanisms that could explain it: nanoflares or Alfvén waves. To date, neither can be directly observed. Nanoflares are, by definition, extremely small, but their aggregate energy release could represent a substantial heating mechanism, presuming they are sufficiently abundant. One way to test this presumption is via the flare frequency distribution, which describes how often flares of various energies occur. If the slope of the power law fitting the flare frequency distribution is above a critical threshold, α = 2 as established in prior literature, then there should be a sufficient abundance of nanoflares to explain coronal heating. We performed >600 case studies of solar flares, made possible by an unprecedented number of data analysts via three semesters of an undergraduate physics laboratory course. This allowed us to include two crucial, but nontrivial, analysis methods: preflare baseline subtraction and computation of the flare energy, which requires determining flare start and stop times. We aggregated the results of these analyses into a statistical study to determine that α = 1.63 ± 0.03. This is below the critical threshold, suggesting that Alfvén waves are an important driver of coronal heating.

Summary: Ants (Hymenoptera: Formicidae) are familiar inhabitants of most terrestrial environments. Although we are aware of the ability of many species to sting, knowledge of ant venom chemistry remains limited. Herein, we describe the discovery and characterization of an O-linked glycopeptide (Mg7a) as a major component of the venom of the ant Myrmecia gulosa. Electron transfer dissociation and higher-energy collisional dissociation tandem mass spectrometry were used to localize three α-N-acetylgalactosaminyl residues (α-GalNAc) present on the 63-residue peptide. To allow for functional studies, we synthesized the full-length glycosylated peptide via solid-phase peptide synthesis, combined with diselenide–selenoester ligation-deselenization chemistry. We show that Mg7a is paralytic and lethal to insects, and triggers pain behavior and inflammation in mammals, which it achieves through a membrane-targeting mode of action. Deglycosylation of Mg7a renders it insoluble in aqueous solution, suggesting a key solubilizing role of the O-glycans.

Prolonged fasting has shown beneficial effects in healthy individuals and in people with chronic diseases. In type 1 diabetes, the effect or even the feasibility of fasting is unclear. We aimed to assess the impact and safety of prolonged fasting in adults with type 1 diabetes. Glycemia was assessed during overnight fasting (12 hours) vs. prolonged fasting (36 hours) via an intermittently-scanned continuous glucose monitoring system. Anthropometric data, metabolic and hormonal markers were compared between both trial arms. After each fasting period, a 75 g oral glucose tolerance test was performed and plasma glucose levels and hormones were assessed. Data were compared via paired t-tests and mixed-model regressions (p ≤ 0.05). Twenty individuals with type 1 diabetes (7 females) with a mean ± SD age of 35 ± 11 years, body mass index (BMI) 24.8 ± 2.8 kg/m2 and HbA1c 54 ± 7 mmol/mol were included. Hypoglycemia/hour (70 mg/dL;

The objective of this paper is to analyse impacts of COVID-19 on the nexus of food systems, the environment and sustainable development and propose ways for governments and international agencies to mitigate impacts in the short and medium term. It covers the historic period from early 2020 to early 2021 and also makes an assessment on future prospects. Although evidence is collected from all around the world, the focus is primarily on developing countries. The methods used are a review of the announced actions and preliminary findings in the academic and grey literature as well as on reliable websites from global and international institutions. By October 2020, governments around the world had invested about $12 trillion to counteract the economic effects of COVID-19. This investment could contribute to progress on the SDGs and global climate targets insofar as it was invested within a framework that supports both socio-economic recovery and sustainability. Initial analysis indicates that investments for economic recovery did not sufficiently address food security and sustainability, concentrating instead on immediate economic risk management. The global sustainable development agenda must promote the resilience and sustainability of food systems through policies and measures that: i) account for environmental thresholds and trade-offs; ii) promote food security and healthy diets; iii) enhance and protect rural livelihoods; and iv) address the inequalities and injustices that have emerged and will prevail during a post-COVID transition. National stimulus programs and the actions of international agencies must be assessed and monitored to deliver multiple benefits simultaneously and guide building back better.

Structured Data Transformation Language (SDTL) provides structured, machine actionable representations of data transformation commands found in statistical analysis software. The Continuous Capture of Metadata for Statistical Data Project (C2Metadata) created SDTL as part of an automated system that captures provenance metadata from data transformation scripts and adds variable derivations to standard metadata files. SDTL also has potential for auditing scripts and for translating scripts between languages. SDTL is expressed in a set of JSON schemas, which are machine actionable and easily serialized to other formats. Statistical software languages have a number of special features that have been carried into SDTL. We explain how SDTL handles differences among statistical languages and complex operations, such as merging files and reshaping data tables from “wide” to “long”.

IntroductionTo investigate the glycaemic response, macronutrient intake and insulin management in people with type 1 diabetes (T1D) compared to healthy individuals around a running competition.Material and methodsThis was a single-centre, prospective, controlled observational study performed in individuals with T1D and healthy people. 24 people (12 T1D) were included in this study (age: T1D 41±12 vs. healthy 38±6 years, females: 3 vs. 6, BMI: 25.53.0 vs. 22.9±2.8 kg/m2). Both groups received an intermittently scanned continuous glucose monitoring (isCGM; FreeStyle Libre 1, Abbott, USA) system to assess glycaemia 24 hours before, during and 24 hours after a running competition. During this period, participants recorded their food intake and insulin administration. Data were analysed via ANOVA and mixed model analyses with post-hoc testing (p≤0.05).ResultsFor overall glycaemic ranges in comparison of groups, significant differences were found for time in range (T1D 63±21% vs. healthy 89±13%, p = 0.001), time above range (TAR) 1 (T1D 21±15% vs. healthy 0±0%, pConclusionPeople with T1D have impaired glucose responses around a running competition compared to healthy individuals. However, basal insulin dose reductions were sufficient to prevent further dysglycaemia.Clinical trial iddrks.de; DRKS00019886.

Abstract Background Therapy must be adapted for people with type 1 diabetes to avoid exercise-induced hypoglycemia caused by increased exercise-related glucose uptake into muscles. Therefore, to avoid hypoglycemia, the preexercise short-acting insulin dose must be reduced for safety reasons. We report a case of a man with long-lasting type 1 diabetes in whom no blood glucose decrease during different types of exercise with varying exercise intensities and modes was found, despite physiological hormone responses. Case presentation A Caucasian man diagnosed with type 1 diabetes for 24 years performed three different continuous high-intensity interval cycle ergometer exercises as part of a clinical trial (ClinicalTrials.gov identifier NCT02075567). Intensities for both modes of exercises were set at 5% below and 5% above the first lactate turn point and 5% below the second lactate turn point. Short-acting insulin doses were reduced by 25%, 50%, and 75%, respectively. Measurements taken included blood glucose, blood lactate, gas exchange, heart rate, adrenaline, noradrenaline, cortisol, glucagon, and insulin-like growth factor-1. Unexpectedly, no significant blood glucose decreases were observed during all exercise sessions (start versus end, 12.97 ± 2.12 versus 12.61 ± 2.66 mmol L−1, p = 0.259). All hormones showed the expected response, dependent on the different intensities and modes of exercises. Conclusions People with type 1 diabetes typically experience a decrease in blood glucose levels, particularly during low- and moderate-intensity exercises. In our patient, we clearly found no decline in blood glucose, despite a normal hormone response and no history of any insulin insensitivity. This report indicates that there might be patients for whom the recommended preexercise therapy adaptation to avoid exercise-induced hypoglycemia needs to be questioned because this could increase the risk of severe hyperglycemia and ketosis.

The peripheral effects of ω-conotoxins, selective blockers of N-type voltage-gated calcium channels (CaV2.2), have not been characterised across different clinically relevant pain models. This study examines the effects of locally administered ω-conotoxin MVIIA, GVIA, and CVIF on mechanical and thermal paw withdrawal threshold (PWT) in postsurgical pain (PSP), cisplatin-induced neuropathy (CisIPN), and oxaliplatin-induced neuropathy (OIPN) rodent models. Intraplantar injection of 300, 100 and 30 nM MVIIA significantly (p < 0.0001, p < 0.0001, and p < 0.05, respectively) alleviated mechanical allodynia of mice in PSP model compared to vehicle control group. Similarly, intraplantar injection of 300, 100, and 30 nM MVIIA (p < 0.0001, p < 0.01, and p < 0.05, respectively), and 300 nM and 100 nM GVIA (p < 0.0001 and p < 0.05, respectively) significantly increased mechanical thresholds of mice in OIPN model. The ED50 of GVIA and MVIIA in OIPN was found to be 1.8 pmol/paw and 0.8 pmol/paw, respectively. However, none of the ω-conotoxins were effective in a mouse model of CisIPN. The intraplantar administration of 300 nM GVIA, MVIIA, and CVIF did not cause any locomotor side effects. The intraplantar administration of MVIIA can alleviate incision-induced mechanical allodynia, and GVIA and MVIIA effectively reduce OIPN associated mechanical pain, without locomotor side effects, in rodent models. In contrast, CVIF was inactive in these pain models, suggesting it is unable to block a subset of N-type voltage-gated calcium channels associated with nociceptors in the skin.

To assess intermittently scanned continuous glucose monitoring (isCGM) performance for different rates of change in plasma glucose (RCPG) during glycemic challenges in type 1 diabetes (T1D). Nineteen people with T1D (7 females; age 35 ± 11 years; HbA1c 7.3 ± 0.6% (56 ± 7 mmol/mol)) performing two glycemic challenges (OGTT) were included. During OGTTs, plasma glucose was compared against sensor glucose for timepoints 0 min (pre-OGTT), +15 min, +30 min, +60 min, +120 min, +180 min, and +240 min by means of median absolute (relative) difference (MARD and MAD) and Clarke Error Grid (CEG), then was stratified for RCPG and glycemic ranges. Overall, MARD was 8.3% (4.0–14.8) during hypoglycemia level 1 18.8% (15.8–22.0), euglycemia 9.5% (4.3–15.1), hyperglycemia level 1 9.4% (4.0–17.2), and hyperglycemia level 2 7.1% (3.3–11.9). The MARD was associated with the RCPG (p < 0.0001), detailing significant differences in comparison of low, moderate, high, and very high RCPG (p = 0.014). Overall, CEG resulted in 88% (212 values) of comparison points in zone A, 12% (29 values) in zone B, and 0.4% (1 value) in zone D. The isCGM system was accurate during OGTTs. Its performance was dependent on the RCPG and showed an overestimation of the actual reference glucose during hypoglycemia.

To investigate the heart rate during cardio-pulmonary exercise (CPX) testing in individuals with type 1 diabetes (T1D) compared to healthy (CON) individuals. Fourteen people (seven individuals with T1D and seven CON individuals) performed a CPX test until volitional exhaustion to determine the first and second lactate turn points (LTP1 and LTP2), ventilatory thresholds (VT1 and VT2), and the heart rate turn point. For these thresholds cardio-respiratory variables and percentages of maximum heart rate, heart rate reserve, maximum oxygen uptake and oxygen uptake reserve, and maximum power output were compared between groups. Additionally, the degree and direction of the deflection of the heart rate to performance curve (kHR) were compared between groups. Individuals with T1D had similar heart rate at LTP1 (mean difference) −11, [(95% confidence interval) −27 to 4 b.min−1], at VT1 (−12, −8 to 33 b.min−1) and at LTP2 (−7, −13 to 26 b.min−1), at VT2 (−7, −13 to 28 b.min−1), and at the heart rate turn point (−5, −14 to 24 b.min−1) (p = 0.22). Heart rate expressed as percentage of maximum heart rate at LTP1, VT1, LTP2, VT2 and the heart rate turn point as well as expressed as percentages of heart rate reserve at LTP2, VT2 and the heart rate turn point was lower in individuals with T1D (p < 0.05). kHR was lower in T1D compared to CON individuals (0.11 ± 0.25 vs. 0.51 ± 0.32, p = 0.02). Our findings demonstrate that there are clear differences in the heart rate response during CPX testing in individuals with T1D compared to CON individuals. We suggest using submaximal markers to prescribe exercise intensity in people with T1D, as the heart rate at thresholds is influenced by kHR.Clinical Trial Identifier: NCT02075567 (https://clinicaltrials.gov/ct2/show/NCT02075567).

We investigated blood glucose (BG) and hormone response to aerobic high-intensity interval exercise (HIIE) and moderate continuous exercise (CON) matched for mean load and duration in type 1 diabetes mellitus (T1DM).Seven trained male subjects with T1DM performed a maximal incremental exercise test and HIIE and CON at 3 different mean intensities below (A) and above (B) the first lactate turn point and below the second lactate turn point (C) on a cycle ergometer. Subjects were adjusted to ultra-long-acting insulin Degludec (Tresiba/ Novo Nordisk, Denmark). Before exercise, standardized meals were administered, and short-acting insulin dose was reduced by 25% (A), 50% (B), and 75% (C) dependent on mean exercise intensity. During exercise, BG, adrenaline, noradrenaline, dopamine, cortisol, glucagon, and insulin-like growth factor-1, blood lactate, heart rate, and gas exchange variables were measured. For 24 h after exercise, interstitial glucose was measured by continuous glucose monitoring system.BG decrease during HIIE was significantly smaller for B (p = 0.024) and tended to be smaller for A and C compared to CON. No differences were found for post-exercise interstitial glucose, acute hormone response, and carbohydrate utilization between HIIE and CON for A, B, and C. In HIIE, blood lactate for A (p = 0.006) and B (p = 0.004) and respiratory exchange ratio for A (p = 0.003) and B (p = 0.003) were significantly higher compared to CON but not for C.Hypoglycemia did not occur during or after HIIE and CON when using ultra-long-acting insulin and applying our methodological approach for exercise prescription. HIIE led to a smaller BG decrease compared to CON, although both exercises modes were matched for mean load and duration, even despite markedly higher peak workloads applied in HIIE. Therefore, HIIE and CON could be safely performed in T1DM.ClinicalTrials.gov NCT02075567 http://www.clinicaltrials.gov/ct2/show/NCT02075567.