Retrieval Practice Improves Exam Performance as a Function of Review Question Number and Format.

INTRODUCTION: Although retrieval practice is a well-established method of improving learning, it is unclear whether review question format matters or how many review questions are needed to maximize the effects of retrieval practice. REVIEW OF LITERATURE: Inconsistent findings are reported regarding review question format, and no studies were conducted in physical therapy education programs. A positive relationship is reported between review question number and exam performance, but no studies estimate the number of review questions needed to maximize retention of specific learning objectives. SUBJECTS: Eighty-eight second-year Doctor of Physical Therapy students (baseline cohort = 42 students, intervention cohort = 46 students). METHODS: Exam questions were randomly assigned into different review categories. Some exam questions received no review, whereas other exam questions were reviewed with open-ended review questions or varying numbers of multiple-choice review questions. Performance on 160 multiple-choice exam questions was compared between review question categories using mixed-effects logistic regression models. RESULTS: Both open-ended and multiple-choice review questions significantly improved exam question performance. Performance on exam questions improved most when more than one multiple-choice review question was provided. After controlling for exam question difficulty, multiple-choice review questions were superior to open-ended review questions. DISCUSSION AND CONCLUSION: On multiple-choice exams, multiple-choice review questions are at least as effective as open-ended review questions. Given their ease of implementation, multiple-choice review questions are an efficient means to improve multiple-choice exam question performance.

A glycolytic metabolite bypasses "two-hit" tumor suppression by BRCA2.

Knudson's "two-hit" paradigm posits that carcinogenesis requires inactivation of both copies of an autosomal tumor suppressor gene. Here, we report that the glycolytic metabolite methylglyoxal (MGO) transiently bypasses Knudson's paradigm by inactivating the breast cancer suppressor protein BRCA2 to elicit a cancer-associated, mutational single-base substitution (SBS) signature in nonmalignant mammary cells or patient-derived organoids. Germline monoallelic BRCA2 mutations predispose to these changes. An analogous SBS signature, again without biallelic BRCA2 inactivation, accompanies MGO accumulation and DNA damage in Kras-driven, Brca2-mutant murine pancreatic cancers and human breast cancers. MGO triggers BRCA2 proteolysis, temporarily disabling BRCA2's tumor suppressive functions in DNA repair and replication, causing functional haploinsufficiency. Intermittent MGO exposure incites episodic SBS mutations without permanent BRCA2 inactivation. Thus, a metabolic mechanism wherein MGO-induced BRCA2 haploinsufficiency transiently bypasses Knudson's two-hit requirement could link glycolysis activation by oncogenes, metabolic disorders, or dietary challenges to mutational signatures implicated in cancer evolution.

Mutational signature assignment heterogeneity is widespread and can be addressed by ensemble approaches.

Single-base substitution (SBS) mutational signatures have become standard practice in cancer genomics. In lieu of de novo signature extraction, reference signature assignment allows users to estimate the activities of pre-established SBS signatures within individual malignancies. Several tools have been developed for this purpose, each with differing methodologies. However, due to a lack of standardization, there may be inter-tool variability in signature assignment. We deeply characterized three assignment strategies and five SBS signature assignment tools. We observed that assignment strategy choice can significantly influence results and interpretations. Despite varying recommendations by tools, Refit performed best by reducing overfitting and maximizing reconstruction of the original mutational spectra. Even after uniform application of Refit, tools varied remarkably in signature assignments both qualitatively (Jaccard index = 0.38-0.83) and quantitatively (Kendall tau-b = 0.18-0.76). This phenomenon was exacerbated for 'flat' signatures such as the homologous recombination deficiency signature SBS3. An ensemble approach (EnsembleFit), which leverages output from all five tools, increased SBS3 assignment accuracy in BRCA1/2-deficient breast carcinomas. After generating synthetic mutational profiles for thousands of pan-cancer tumors, EnsembleFit reduced signature activity assignment error 15.9-24.7% on average using Catalogue of Somatic Mutations In Cancer and non-standard reference signature sets. We have also released the EnsembleFit web portal (https://www.ensemblefit.pittlabgenomics.com) for users to generate or download ensemble-based SBS signature assignments using any strategy and combination of tools. Overall, we show that signature assignment heterogeneity across tools and strategies is non-negligible and propose a viable, ensemble solution.

Patterns of Oncogene Coexpression at Single-Cell Resolution Influence Survival in Lymphoma.

Cancers often overexpress multiple clinically relevant oncogenes, but it is not known if combinations of oncogenes in cellular subpopulations within a cancer influence clinical outcomes. Using quantitative multispectral imaging of the prognostically relevant oncogenes MYC, BCL2, and BCL6 in diffuse large B-cell lymphoma (DLBCL), we show that the percentage of cells with a unique combination MYC+BCL2+BCL6- (M+2+6-) consistently predicts survival across four independent cohorts (n = 449), an effect not observed with other combinations including M+2+6+. We show that the M+2+6- percentage can be mathematically derived from quantitative measurements of the individual oncogenes and correlates with survival in IHC (n = 316) and gene expression (n = 2,521) datasets. Comparative bulk/single-cell transcriptomic analyses of DLBCL samples and MYC/BCL2/BCL6-transformed primary B cells identify molecular features, including cyclin D2 and PI3K/AKT as candidate regulators of M+2+6- unfavorable biology. Similar analyses evaluating oncogenic combinations at single-cell resolution in other cancers may facilitate an understanding of cancer evolution and therapy resistance. SIGNIFICANCE: Using single-cell-resolved multiplexed imaging, we show that selected subpopulations of cells expressing specific combinations of oncogenes influence clinical outcomes in lymphoma. We describe a probabilistic metric for the estimation of cellular oncogenic coexpression from IHC or bulk transcriptomes, with possible implications for prognostication and therapeutic target discovery in cancer. This article is highlighted in the In This Issue feature, p. 1027.

Noncognitive Factors of Grit and Mindset Do Not Predict Performance on the National Physical Therapy Exam.

INTRODUCTION: National Physical Therapy Exam (NPTE) performance is predicted to some degree by cognitive measures, such as grade point average (GPA) and the Graduate Record Exam scores. Researchers have begun to explore noncognitive measures, for example, grit and mindset, which could account for other potential determinants of student success in physical therapist (PT) education programs and the NPTE. REVIEW OF LITERATURE: There is a paucity of evidence that has explored non-cognitive factors related to academic performance compared to cognitive factors. Constructs such as grit and mindset have been identified as reliable measures; however, mixed results occur in the literature as how these scales predict NPTE performance. Cognitive factors continue to demonstrate stronger correlations to NPTE performance. SUBJECTS: Four PT student cohorts (n = 43, 45, 50, and 49) were enrolled in a prospective cohort study. METHODS: Grit and mindset were measured by self-reported questionnaires. Cognitive measures were obtained, including undergraduate cumulative GPA (cGPA), undergraduate science GPA (sGPA), graduate GPA (gGPA), Academic Practice Exam and Assessment Tool (Academic PEAT) scores, and NPTE scores. Pairwise Pearson's correlation coefficients were calculated for each cohort. National Physical Therapy Exam scores from 2 graduating cohorts were analyzed using multiple linear regression to identify variables that predicted successful outcomes. RESULTS: Neither grit nor mindset correlated with any cognitive measures. Furthermore, neither grit nor mindset were significantly associated with NPTE scores or outcomes in multivariate regression models. National Physical Therapy Exam scores were significantly associated with gGPA (ß = 148.4, 95% confidence interval [CI] = 93.4-203.5) and Academic PEAT scores (ß = 0.28, 95% CI = 0.08-0.49). DISCUSSION AND CONCLUSION: Among PT students at a small liberal arts institution in the midwest, grit and mindset were not associated with any indicators of academic success (e.g., cGPA, sGPA, gGPA, Academic PEAT, or NPTE scores). NPTE outcomes were best predicted by gGPA and Academic PEAT scores. These findings conflict with previous reports that grit and mindset are potential markers for academic success and support monitoring gGPA and Academic PEAT scores to identify students who may require additional preparation before sitting for the NPTE.

Dependence of learning outcomes in flipped and lecture classrooms on review questions: A randomized controlled trial and observational study.

PURPOSE: The effects of class structure (i.e., lecture vs. flipped) and repeated review on: 1) exam scores and 2) student perceptions of learning were compared in a prospective randomized controlled trial (Study 1) and a retrospective cohort study (Study 2). METHODS: In Study 1, 42 second year students in a Doctor of Physical Therapy program were randomized to either a lecture or flipped section of a neurobiology class. Both sections incorporated repeated review. In Study 2, exam scores were retrospectively compared between two cohorts: a lecture cohort without repeated review (n = 42) and a flipped cohort with repeated review (n = 46). In both studies, outcomes of interest were exam scores and student surveys. RESULTS: In Study 1, students in the lecture and flipped sections had similar exam averages (lecture = 76.7 ± 17%, flipped = 77.5 ± 17%, p = 0.73). Repeated review significantly improved exam scores by 12.0 percentage points (95% CI: 8.0 to 16.0 percentage points) in the lecture section and 10.8 percentage points (95% CI: 6.9 to 14.8 percentage points) in the flipped section. The flipped section reported higher levels of satisfaction and perceived learning. In Study 2, the flipped cohort had significantly higher exam scores than the lecture cohort (lecture = 70.2 ± 6.9%, flipped = 83.4 ± 7.7%, p < 0.0001). Student satisfaction and perceived learning were similar in both cohorts. CONCLUSION: Exam scores improve with review questions and quizzes provided in a class, both in a lecture or flipped classroom.

Nutritional intake when cycling under racing and training conditions in professional male cyclists with type 1 diabetes.

This study sought to detail and compare the in-ride nutritional practices of a group of professional cyclists with type 1 diabetes (T1D) under training and racing conditions. We observed seven male professional road cyclists with T1D (Age: 28 ± 4 years, HbA1c: 6.4 ± 0.4% [46 ± 4 mmol.mol-1], VO2max: 73.9 ± 4.3 ml.kg -1.min-1) during pre-season training and during a Union Cycliste Internationale multi-stage road cycling race (Tour of Slovenia). In-ride nutritional, interstitial glucose, and performance variables were quantified and compared between the two events.    The in-ride energy intake was similar between training and racing conditions     (p = 0.909), with carbohydrates being the major source of fuel in both events during exercise at a rate of 41.9 ± 6.8 g.h-1 and 45.4 ± 15.5 g.h-1 (p = 0.548), respectively. Protein consumption was higher during training (2.6 ± 0.6 g.h-1) than race rides (1.9 ± 0.9 g.h-1; p = 0.051).   A similar amount of time was spent within the euglycaemic range (≥70-≤180 mg.dL-1): training 77.1 ± 32.8% vs racing 73.4 ± 3.9%; p = 0.818. These data provide new information on the in-ride nutritional intake in professional cyclists with T1D during different stages of the competitive season.

Evidence that conserved essential genes are enriched for pro-longevity factors.

At the cellular level, many aspects of aging are conserved across species. This has been demonstrated by numerous studies in simple model organisms like Saccharomyces cerevisiae, Caenorhabdits elegans, and Drosophila melanogaster. Because most genetic screens examine loss of function mutations or decreased expression of genes through reverse genetics, essential genes have often been overlooked as potential modulators of the aging process. By taking the approach of increasing the expression level of a subset of conserved essential genes, we found that 21% of these genes resulted in increased replicative lifespan in S. cerevisiae. This is greater than the ~ 3.5% of genes found to affect lifespan upon deletion, suggesting that activation of essential genes may have a relatively disproportionate effect on increasing lifespan. The results of our experiments demonstrate that essential gene overexpression is a rich, relatively unexplored means of increasing eukaryotic lifespan.

Pan-cancer pervasive upregulation of 3' UTR splicing drives tumourigenesis.

Most mammalian genes generate messenger RNAs with variable untranslated regions (UTRs) that are important post-transcriptional regulators. In cancer, shortening at 3' UTR ends via alternative polyadenylation can activate oncogenes. However, internal 3' UTR splicing remains poorly understood as splicing studies have traditionally focused on protein-coding alterations. Here we systematically map the pan-cancer landscape of 3' UTR splicing and present this in SpUR ( http://www.cbrc.kaust.edu.sa/spur/home/ ). 3' UTR splicing is widespread, upregulated in cancers, correlated with poor prognosis and more prevalent in oncogenes. We show that antisense oligonucleotide-mediated inhibition of 3' UTR splicing efficiently reduces oncogene expression and impedes tumour progression. Notably, CTNNB1 3' UTR splicing is the most consistently dysregulated event across cancers. We validate its upregulation in hepatocellular carcinoma and colon adenocarcinoma, and show that the spliced 3' UTR variant is the predominant contributor to its oncogenic functions. Overall, our study highlights the importance of 3' UTR splicing in cancer and may launch new avenues for RNA-based anti-cancer therapeutics.

Passing on the exercise baton: What can endocrine patients learn from elite athletes?

As elite athletes demonstrate through the Olympic motto 'Citius, Altius, Fortius- Communiter', new performance records are driven forward by favourable skeletal muscle bioenergetics, cardiorespiratory, and endocrine system adaptations. At a recreational level, regular physical activity is an effective nonpharmacological therapy in the treatment of many endocrine conditions. However, the impact of physical exercise on endocrine function and how best to incorporate exercise therapy into clinical care are not well understood. Beyond the pursuit of an Olympic medal, elite athletes may therefore serve as role models for showcasing how exercise can help in the management of endocrine disorders and improve metabolic dysfunction. This review summarizes research evidence for clinicians who wish to understand endocrine changes in athletes who already perform high levels of activity as well as to encourage patients to exercise more safely. Herein, we detail the upper limits of athleticism to showcase the adaptability of human endocrine-metabolic-physiological systems. Then, we describe the growing research base that advocates the importance of understanding maladaptation to physical training and nutrition in males and females; especially the young. Finally, we explore the impact of physical activity in improving some endocrine disorders with guidance on how lessons can be taken from athletes training and incorporated into strategies to move more people more often.

Immune pathway upregulation and lower genomic instability distinguish EBV-positive nodal T/NK-cell lymphoma from ENKTL and PTCL-NOS.

Primary Epstein-Barr virus (EBV)-positive nodal T/NK-cell lymphoma (PTCL-EBV) is a poorly understood disease which shows features resembling extranodal NK/T-cell lymphoma (ENKTL) and is currently not recognized as a distinct entity but categorized as a variant of primary T-cell lymphoma not otherwise specified (PTCL-NOS). Herein, we analyzed copynumber aberrations (n=77) with a focus on global measures of genomic instability and homologous recombination deficiency and performed gene expression (n=84) and EBV miRNA expression (n=24) profiling as well as targeted mutational analysis (n=16) to further characterize PTCL-EBV in relation to ENKTL and PTCL-NOS. Multivariate analysis revealed that patients with PTCL-EBV had a significantly worse outcome compared to patients with PTCL-NOS (P=0.002) but not to those with ENKTL. Remarkably, PTCL-EBV exhibited significantly lower genomic instability and homologous recombination deficiency scores compared to ENKTL and PTCL-NOS. Gene set enrichment analysis revealed that many immune-related pathways, interferon α/γ response, and IL6_JAK_STAT3 signaling were significantly upregulated in PTCLEBV and correlated with lower genomic instability scores. We also identified that NFκB-associated genes, BIRC3, NFKB1 (P50) and CD27, and their proteins are upregulated in PTCL-EBV. Most PTCL-EBV demonstrated a type 2 EBV latency pattern and, strikingly, exhibited downregulated expression of most EBV miRNA compared to ENKTL and their target genes were also enriched in immune-related pathways. PTCL-EBV also showed frequent mutations of TET2, PIK3CD and STAT3, and are characterized by microsatellite stability. Overall, poor outcome, low genomic instability, upregulation of immune pathways and downregulation of EBV miRNA are distinctive features of PTCL-EBV. Our data support the concept that PTCL-EBV could be considered as a distinct entity, provide novel insights into the pathogenesis of the disease and offer potential new therapeutic targets for this tumor.

Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes.

Black women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.

Pancreatic ß-Cell Function Is Associated with Augmented Counterregulation to In-Exercise Hypoglycemia in Type 1 Diabetes.

PURPOSE: This study aimed to investigate the influence of residual ß-cell function on counterregulatory hormonal responses to hypoglycemia during acute physical exercise in people with type 1 diabetes (T1D). A secondary aim was to explore relationships between biomarkers of pancreatic ß-cell function and indices of glycemia following acute exercise including the nocturnal period. METHODS: This study involved an exploratory, secondary analysis of data from individuals with T1D who partook in a four-peroid, randomized, cross-over trial involving a bout of evening exercise followed by an overnight stay in a clinical laboratory facility. Participants were split into two groups: (i) a stimulated C-peptide level of ≥30 pmol⋅L-1 (low-level secretors [LLS], n = 6) or (ii) <30 pmol⋅L-1 (microsecretors [MS], n = 10). Pancreatic hormones (C-peptide, proinsulin, and glucagon), catecholamines (epinephrine [EPI] and norepinephrine [NE]), and metabolic biomarkers (blood glucose, blood lactate, and ß-hydroxybutyrate) were measured at rest, during exercise with and without a hypoglycemic (blood glucose ≤3.9 mmol⋅L-1) episode, and throughout a 13-h postexercise period. Interstitial glucose monitoring was used to assess indices of glycemic variability. RESULTS: During in-exercise hypoglycemia, LLS presented with greater sympathoadrenal (EPI and NE P ≤ 0.05) and ketone (P < 0.01) concentrations. Glucagon remained similar (P = 0.09). Over exercise, LLS experienced larger drops in C-peptide and proinsulin (both P < 0.01) as well as greater increases in EPI (P < 0.01) and ß-hydroxybutyrate (P = 0.03). LLS spent less time in the interstitial-derived hypoglycemic range acutely postexercise and had lower glucose variability throughout the nocturnal period. CONCLUSION: Higher residual ß-cell function was associated with greater sympathoadrenal and ketonic responses to exercise-induced hypoglycemia as well as improved glycemia leading into and throughout the nocturnal hours. Even a minimal amount of residual ß-cell function confers a beneficial effect on glycemic outcomes during and after exercise in people with T1D.

Highly recurrent CBS epimutations in gastric cancer CpG island methylator phenotypes and inflammation.

BACKGROUND: CIMP (CpG island methylator phenotype) is an epigenetic molecular subtype, observed in multiple malignancies and associated with the epigenetic silencing of tumor suppressors. Currently, for most cancers including gastric cancer (GC), mechanisms underlying CIMP remain poorly understood. We sought to discover molecular contributors to CIMP in GC, by performing global DNA methylation, gene expression, and proteomics profiling across 14 gastric cell lines, followed by similar integrative analysis in 50 GC cell lines and 467 primary GCs. RESULTS: We identify the cystathionine beta-synthase enzyme (CBS) as a highly recurrent target of epigenetic silencing in CIMP GC. Likewise, we show that CBS epimutations are significantly associated with CIMP in various other cancers, occurring even in premalignant gastroesophageal conditions and longitudinally linked to clinical persistence. Of note, CRISPR deletion of CBS in normal gastric epithelial cells induces widespread DNA methylation changes that overlap with primary GC CIMP patterns. Reflecting its metabolic role as a gatekeeper interlinking the methionine and homocysteine cycles, CBS loss in vitro also causes reductions in the anti-inflammatory gasotransmitter hydrogen sulfide (H2S), with concomitant increase in NF-κB activity. In a murine genetic model of CBS deficiency, preliminary data indicate upregulated immune-mediated transcriptional signatures in the stomach. CONCLUSIONS: Our results implicate CBS as a bi-faceted modifier of aberrant DNA methylation and inflammation in GC and highlights H2S donors as a potential new therapy for CBS-silenced lesions.

Quantitative imaging of RAD51 expression as a marker of platinum resistance in ovarian cancer.

Early relapse after platinum chemotherapy in epithelial ovarian cancer (EOC) portends poor survival. A-priori identification of platinum resistance is therefore crucial to improve on standard first-line carboplatin-paclitaxel treatment. The DNA repair pathway homologous recombination (HR) repairs platinum-induced damage, and the HR recombinase RAD51 is overexpressed in cancer. We therefore designed a REMARK-compliant study of pre-treatment RAD51 expression in EOC, using fluorescent quantitative immunohistochemistry (qIHC) to overcome challenges in quantitation of protein expression in situ. In a discovery cohort (n = 284), RAD51-High tumours had shorter progression-free and overall survival compared to RAD51-Low cases in univariate and multivariate analyses. The association of RAD51 with relapse/survival was validated in a carboplatin monotherapy SCOTROC4 clinical trial cohort (n = 264) and was predominantly noted in HR-proficient cancers (Myriad HRDscore < 42). Interestingly, overexpression of RAD51 modified expression of immune-regulatory pathways in vitro, while RAD51-High tumours showed exclusion of cytotoxic T cells in situ. Our findings highlight RAD51 expression as a determinant of platinum resistance and suggest possible roles for therapy to overcome immune exclusion in RAD51-High EOC. The qIHC approach is generalizable to other proteins with a continuum instead of discrete/bimodal expression.

Blood Glucose Responses during Cardiopulmonary Incremental Exercise Testing in Type 1 Diabetes: A Pooled Analysis.

PURPOSE: This study aimed to determine the glycemic responses to cardiopulmonary exercise testing (CPET) in individuals with type 1 diabetes (T1D) and to explore the influence of starting blood glucose (BG) concentrations on subsequent CPET outcomes. METHODS: This study was a retrospective, secondary analysis of pooled data from three randomized crossover trials using identical CPET protocols. During cycling, cardiopulmonary variables were measured continuously, with BG and lactate values obtained minutely via capillary earlobe sampling. Anaerobic threshold was determined using ventilatory parameters. Participants were split into (i) euglycemic ([Eu] >3.9 to ≤10.0 mmol·L-1, n = 26) and (ii) hyperglycemic ([Hyper] >10.0 mmol·L-1, n = 10) groups based on preexercise BG concentrations. Data were assessed via general linear modeling techniques and regression analyses. P values of ≤0.05 were accepted as significant. RESULTS: Data from 36 individuals with T1D (HbA1c, 7.3% ± 1.1% [56.0 ± 11.5 mmol·mol-1]) were included. BG remained equivalent to preexercise concentrations throughout CPET, with an overall change in BG of -0.32 ± 1.43 mmol·L-1. Hyper had higher HR at peak (+10 ± 2 bpm, P = 0.04) and during recovery (+9 ± 2 bpm, P = 0.038) as well as lower O2 pulse during the cool down period (-1.6 ± 0.04 mL per beat, P = 0.021). BG responses were comparable between glycemic groups. Higher preexercise BG led to greater lactate formation during exercise. HbA1c was inversely related to time to exhaustion (r = -0.388, P = 0.04) as well as peak power output (r = -0.355, P = 0.006) and O2 pulse (r = -0.308, P = 0.015). CONCLUSIONS: This study demonstrated 1) stable BG responses to CPET in patients with T1D; 2) although preexercise hyperglycemia did not influence subsequent glycemic dynamics, it did potentiate alterations in various cardiac and metabolic responses to CPET; and 3) HbA1c was a significant factor in the determination of peak performance outcomes during CPET.

Extent and prevalence of post-exercise and nocturnal hypoglycemia following peri-exercise bolus insulin adjustments in individuals with type 1 diabetes.

AIM: To detail the extent and prevalence of post-exercise and nocturnal hypoglycemia following peri-exercise bolus insulin dose adjustments in individuals with type 1 diabetes (T1D) using multiple daily injections of insulins aspart (IAsp) and degludec (IDeg). METHODS AND RESULTS: Sixteen individuals with T1D, completed a single-centred, randomised, four-period crossover trial consisting of 23-h inpatient phases. Participants administered either a regular (100%) or reduced (50%) dose (100%; 5.1 ± 2.4, 50%; 2.6 ± 1.2 IU, p < 0.001) of individualised IAsp 1 h before and after 45-min of evening exercise at 60 ± 6% V̇O2max. An unaltered dose of IDeg was administered in the morning. Metabolic, physiological and hormonal responses during exercise, recovery and nocturnal periods were characterised. The primary outcome was the number of trial day occurrences of hypoglycemia (venous blood glucose ≤ 3.9 mmol L -1). Inclusion of a 50% IAsp dose reduction strategy prior to evening exercise reduced the occurrence of in-exercise hypoglycemia (p = 0.023). Mimicking this reductive strategy in the post-exercise period decreased risk of nocturnal hypoglycemia (p = 0.045). Combining this strategy to reflect reductions either side of exercise resulted in higher glucose concentrations in the acute post-exercise (p = 0.034), nocturnal (p = 0.001), and overall (p < 0.001) periods. Depth of hypoglycemia (p = 0.302), as well as ketonic and counter-regulatory hormonal profiles were similar. CONCLUSIONS: These findings demonstrate the glycemic safety of peri-exercise bolus dose reduction strategies in minimising the prevalence of acute and nocturnal hypoglycemia following evening exercise in people with T1D on MDI. Use of newer background insulins with current bolus insulins demonstrates efficacy and advances current recommendations for safe performance of exercise. CLINICAL TRIALS REGISTER: DRKS00013509.

Factors Influencing Insulin Absorption Around Exercise in Type 1 Diabetes.

International charities and health care organizations advocate regular physical activity for health benefit in people with type 1 diabetes. Clinical expert and international diabetes organizations' position statements support the management of good glycemia during acute physical exercise by adjusting exogenous insulin and/or carbohydrate intake. Yet research has detailed, and patients frequently report, variable blood glucose responses following both the same physical exercise session and insulin to carbohydrate alteration. One important source of this variability is insulin delivery to the circulation. With modern insulin analogs, it is important to understand how different insulins, their delivery methods, and inherent physiological factors, influence the reproducibility of insulin absorption from the injection site into circulation. Furthermore, contrary to the adaptive pancreatic response to exercise in the person without diabetes, the physiological and metabolic shifts with exercise may increase circulating insulin concentrations that may contribute to exercise-related hyperinsulinemia and consequent hypoglycemia. Thus, a furthered understanding of factors underpinning insulin delivery may offer more confidence for healthcare professionals and patients when looking to improve management of glycemia around exercise.