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Oral semaglutide (Rybelsus ® ) is a glucagon-like peptide-1 (GLP-1) receptor agonist (GLP-1RA) with 94% homology to human GLP-1. It is the first GLP-1RA developed for oral administration, and it comprises a co-formulation of the peptide semaglutide with the absorption enhancer sodium N -(8-[2-hydroxybenzoyl] amino) caprylate, which overcomes the challenges of peptide absorption in the acidic conditions of the stomach. Oral semaglutide is indicated for use as an add-on combination therapy (with other glucose-lowering agents, including insulin) or as a monotherapy (in patients who are intolerant to metformin) for type 2 diabetes when diet and exercise do not provide adequate glycemic control. In an extensive phase III clinical program including patients from across the disease spectrum, treatment with oral semaglutide resulted in effective glycemic control, reductions in body weight, and decreases in systolic blood pressure when used as monotherapy or in combination with other glucose-lowering therapies. Studies showed that oral semaglutide was well tolerated, with a safety profile consistent with the GLP-1RA drug class. The risk of hypoglycemia was low, and the most common adverse events were gastrointestinal, with nausea and diarrhea generally being the most frequently reported manifestations. Cardiovascular (CV) safety was shown to be noninferior to placebo and observations suggest that the CV profile of oral semaglutide is likely to be similar to that of subcutaneous semaglutide. The evolution of the GLP-1RA class to include an oral agent could facilitate the use of these agents earlier in the diabetes treatment cascade owing to wider acceptance from patients and healthcare professionals. Video abstract EgvuffWn6MiD8neB8Lhdz8

Insulin and glucagon exert opposing effects on glucose metabolism and, consequently, pancreatic islet β-cells and α-cells are considered functional antagonists. The intra-islet hypothesis has previously dominated the understanding of glucagon secretion, stating that insulin acts to inhibit the release of glucagon. By contrast, glucagon is a potent stimulator of insulin secretion and has been used to test β-cell function. Over the past decade, α-cells have received increasing attention due to their ability to stimulate insulin secretion from neighbouring β-cells, and α-cell–β-cell crosstalk has proven central for glucose homeostasis in vivo. Glucagon is not only the counter-regulatory hormone to insulin in glucose metabolism but also glucagon secretion is more susceptible to changes in the plasma concentration of certain amino acids than to changes in plasma concentrations of glucose. Thus, the actions of glucagon also include a central role in amino acid turnover and hepatic fat oxidation. This Review provides insights into glucagon secretion, with a focus on the local paracrine actions on glucagon and the importance of α-cell–β-cell crosstalk. We focus on dysregulated glucagon secretion in obesity, non-alcoholic fatty liver disease and type 2 diabetes mellitus. Lastly, the future potential of targeting hyperglucagonaemia and applying dual and triple receptor agonists with glucagon receptor-activating properties in combination with incretin hormone receptor agonism is discussed.This Review highlights mechanisms of glucagon secretion from pancreatic α-cells, including paracrine actions in islets and α-cell–β-cell crosstalk. Dysregulated glucagon secretion in metabolic diseases is also considered and the clinical potential of targeting glucagon is discussed.

Sprint-interval training (SIT) is efficient at improving maximal aerobic capacity and anaerobic fitness at sea-level and may be a feasible training strategy at altitude. Here, it was evaluated if SIT intensity can be maintained in mild to moderate hypoxia. It was hypothesized that 6 x 30 s Wingate sprint performance with 2 min active rest between sprints can be performed in hypoxic conditions corresponding to ~3,000 m of altitude without reducing mean power output (MPO). In a single-blinded, randomized crossover design, ten highly-trained male endurance athletes with a maximal oxygen uptake ( V ˙ O 2max ) of 68 ± 5 mL O 2 × min -1 × kg -1 completed 6 x 30 s all-out Wingate cycling sprints separated by two-minute active recovery on four separate days in a hypobaric chamber. The ambient pressure within the chamber on each experimental day was 772 mmHg (~0 m), 679 mmHg (~915 m), 585 mmHg (~ 2,150 m), and 522 mmHg (~3,050 m), respectively. MPO was not different at sea-level and up to ~2,150 m (~1% and ~3% non-significant decrements at ~915 and ~2,150 m, respectively), whereas MPO was ~5% lower (P<0.05) at ~3,050 m. Temporal differences between altitudes was not different for peak power output (PPO), despite a main effect of altitude. In conclusion, repeated Wingate exercise can be completed by highly-trained athletes at altitudes up to ~2,150 m without compromising MPO or PPO. In contrast, MPO was compromised in hypobaric hypoxia corresponding to ~3,050 m. Thus, SIT may be an efficient strategy for athletes sojourning to moderate altitude and aiming to maintain training quality.

Introduction Determination of blood volume (BV) using the dual‐isotope (e.g., 99mTc‐labeled red blood cells [99mTc‐RBC] and 125I‐labeled human serum albumin [125I‐HSA]) injection method is limited in medicine due to the long isotope half‐life. However, BV has been determined in laboratory settings for 100 years using the carbon monoxide (CO)‐rebreathing‐based procedure, which allows frequent BV measurements. Methods We investigated the reliability and accuracy of a semi‐automated CO‐rebreathing device by comparing it against the dual‐isotope methodology and its ability to detect a known blood removal. In study A, BV was determined three times in ~2 h; twice using the device with rebreathing protocols lasting 2 (CO2min) and 10 min (CO10min) and once with the dual‐isotope technique. In study B, the accuracy of the device was assessed by its ability to detect a 2% removal of BV. Results A good correlation was observed between both the CO‐rebreathing protocols (r2 = 0.89–0.98; p < 0.001) and the dual‐isotope approach (r2 = 0.89–0.95; p < 0.001). In absolute terms BV was 425 ± 263 mL and 491 ± 388 mL lower (p < 0.001) when quantified with the dual‐isotope compared to the CO‐rebreathing protocols. When reducing BV by 132 ± 25 mL (2%), the device quantified a lower (p < 0.001) BV of 150 ± 45 mL. Conclusion This study emphasizes that the semi‐automated device accurately determines small changes (i.e., 2%) in BV and that a high correlation with the dual‐isotope methodology exists. The findings are clinically relevant owing to the method's simple and fast nature (the absence of radioactive tracers and reduced time requirements, i.e., ~15 min vs. ~180 min) and the possibility for repeated measurements within a single day. The cumbersome nature of the dual‐isotope (e.g., 99mTc and 125I‐HSA) injection method has limited the widespread use of blood volume (BV) evaluation in medicine. However, BV has been determined in laboratory settings for centuries using a reliable and rapid carbon monoxide (CO)‐rebreathing‐based procedure. Here, the reliability and accuracy of a newly developed semi‐automated CO‐rebreathing device was investigated by comparing it against the dual‐isotope methodology and its ability to detect a known blood removal. In study A, BV was determined three times within a single day; twice with the device with rebreathing protocols lasting 2 (CO2min) and 10 minutes (CO10min) and once with the dual‐isotope technique. In study B, the accuracy of the device was assessed by its ability to detect a 2% removal of BV. A good correlation (r2 = 0.89–0.95; p < 0.001) was observed between both the CO‐rebreathing protocols versus the dual‐isotope approach and between the two CO‐rebreathing protocols (r2 = 0.89–0.98; p < 0.001). However, in absolute terms BV was 425 ± 263 mL and 491 ± 388 mL lower (p < 0.001) when quantified with the dual‐isotope compared to the CO‐rebreathing protocols. When reducing BV by 132 ± 25 mL (2%), the device accurately quantified a lower (p < 0.001) BV and determined this reduction being 150 ± 45 mL. This study emphasizes the high precision and accuracy of the device and a high correlation with the dual‐isotope methodology. The findings are clinically relevant owing to the device simple and fast nature (the absence of radioactive tracers and reduced time requirements, i.e., ~15 min vs. ~180 min) and the possibility for repeated measurements within a single day.

It is becoming increasingly evident that the myriad of microbes in the gut, within cells and attached to body parts (or roots of plants), play crucial roles for the host. Although this has been known for decades, recent developments in molecular biology allow for expanded insight into the abundance and function of these microbes. Here we used the vinegar fly, Drosophila melanogaster , to investigate fitness measures across the lifetime of flies fed a suspension of gut microbes harvested from young or old flies, respectively. Our hypothesis was that flies constitutively enriched with a ‘Young microbiome’ would live longer and be more agile at old age (i.e. have increased healthspan) compared to flies enriched with an ‘Old microbiome’. Three major take home messages came out of our study: (1) the gut microbiomes of young and old flies differ markedly; (2) feeding flies with Young and Old microbiomes altered the microbiome of recipient flies and (3) the two different microbial diets did not have any effect on locomotor activity nor lifespan of the recipient flies, contradicting our working hypothesis. Combined, these results provide novel insight into the interplay between hosts and their microbiomes and clearly highlight that the phenotypic effects of gut transplants and probiotics can be complex and unpredictable.

Background. Routine vaccines may have nonspecific effects on mortality. An observational study found that OPV given at birth (OPV0) was associated with increased male infant mortality. We investigated the effect of OPV0 on infant mortality in a randomized trial in Guinea-Bissau. Methods. A total of 7012 healthy normal-birth-weight neonates were randomized to BCG only (intervention group) or OPV0 with BCG (usual practice). All children were to receive OPV with pentavalent vaccine (diphtheria, tetanus, pertussis, Haemophilus influenzae type b, and hepatitis B) at 6, 10, and 14 weeks of age. Seven national OPV campaigns were also conducted during the trial period. Children were followed to age 12 months. We used Cox regression to calculate hazard ratios (HRs) for mortality. Results. The trial contradicted the original hypothesis about OPV0 increasing male infant mortality. Within 12 months, 73 children in the BCG + OPV group and 87 children in the BCG-only group died, all from infectious diseases. Comparing BCG + OPV0 vs BCG only, the HR was 0.83 (95% confidence interval [CI], .61–1.13): 0.72 (95% CI, .47–1.10) in boys and 0.97 (95% CI, .61–1.54) in girls. For children enrolled within the first 2 days of life, the HR for BCG + OPV0 vs BCG only was 0.58 (95% CI, .38–.90). From enrollment until the time of OPV campaigns, the HR was 0.68 (95% CI, .45–1.00), the beneficial effect being separately significant for males (0.55 [95% CI, .32–.95]), Conclusions. This is the only randomized trial of the effect of OPV0 on mortality. OPV0 may be associated with nonspecific protection against infectious disease mortality, particularly when given early in life. There are reasons to monitor mortality when OPV is being phased out. Clinical Trials Registration. NCT00710983.

Cancer of unknown primary (CUP) tumors are biologically very heterogeneous, which complicates stratification of patients for treatment. Consequently, these patients face limited treatment options and a poor prognosis. With this study, we aim to expand on the current knowledge of CUP biology by analyzing two cohorts: a well‐characterized cohort of 44 CUP patients, and 213 metastatic patients with known primary. These cohorts were treated at the same institution and characterized by identical molecular assessments. Through comparative analysis of genomic and transcriptomic data, we found that CUP tumors were characterized by high expression of immune‐related genes and pathways compared to other metastatic tumors. Moreover, CUP tumors uniformly demonstrated high levels of tumor‐infiltrating leukocytes and circulating T cells, indicating a strong immune response. Finally, the genetic landscape of CUP tumors resembled that of other metastatic cancers and demonstrated mutations in established cancer genes. In conclusion, CUP tumors possess a distinct immunophenotype that distinguishes them from other metastatic cancers. These results may suggest an immune response in CUP that facilitates metastatic tumor growth while limiting growth of the primary tumor. Cancer of unknown primary (CUP) is a metastatic cancer characterized by no detectable primary tumor. By performing transcriptomic and genomic analysis of CUP tumors and metastatic cancers of known primary, this study finds that CUP tumors exhibit elevated expression of immune‐related genes and pathways, higher levels of tumor‐infiltrating leukocytes and circulating T cells, and non‐distinctive mutations in established cancer genes.

The SHFT device is a novel running wearable consisting of two pods connected to your smartphone issuing several running metrics based on accelerometer and gyroscope technology. The purpose of this study was to investigate the reliability and validity of the power output (PO) metric produced by the SHFT device. To assess reliability, 12 men ran on an outdoor track at 10.5 km·h−1 and 12 km·h−1 on two consecutive days. To assess validity, oxygen uptake (VO2) and SHFT data from eight men and seven women were collected during incremental submaximal running tests on an indoor treadmill on one to four separate days (34 tests in total). SHFT reliability on the outdoor track was strong with coefficients of variance (CV) of 1.8% and 2.4% for 10.5 and 12 km·h−1, respectively. We observed a very strong linear relationship between PO and VO2 (r2 = 0.54) within subjects, and a very strong linear relationship within each subject within each treadmill test (r2 = 0.80). We conclude that SHFT provides a reliable running power estimate and that a very strong relationship between SHFT-Power and metabolic rate exists, which places SHFT as one of the leading commercially available running power meters.

The aim of this randomised controlled trial was to investigate the effects of breakfast high or low in protein on body composition and cardiometabolic markers in young women with overweight. In total, fifty-six women aged 18–30 years consumed a breakfast containing either high protein (34 g protein, n 26) or low protein (6 g protein, n 30) for 12 weeks. Measurements of body composition by dual-energy X-ray absorptiometry, waist circumference, glucose tolerance, fasting glucose, insulin and lipid profile were performed before and after this period. The primary outcome was fat mass. Satiety and hunger were evaluated by self-reported Visual Analogue Scale (VAS) scores. Dietary intake was estimated by 4-d dietary records, and calcium intake was estimated by FFQ. At baseline, relative daily protein intake was 15·2 ± 2·8 E%, which increased to 19·3 ± 3·4 E% in high protein but was unchanged in low protein (P < 0·001 between groups). High protein reported higher satiety compared with low protein (P = 0·02). Yet, no group differences were observed in changes in energy intake, body composition, blood lipid profile or measures of glucose tolerance (all P > 0·10). However, bone mineral content tended to increase in high protein (P = 0·05) and decrease in low protein (P = 0·07, interaction effect: P = 0·01). Conclusively, a high v. low content of protein in breakfast increased satiety but did not affect body composition or cardiometabolic markers in young women with overweight. This study adds to the sparse evidence on the effects of breakfast with different macronutrient compositions on health parameters in women with overweight. Registered at clinicaltrials.gov: NCT04518605.

Some have questioned the evidence for performance-enhancing effects of several substances included on the World Anti-Doping Agency’s Prohibited List due to the divergent or inconclusive findings in randomized controlled trials (RCTs). However, inductive statistical inference based on RCTs-only may result in biased conclusions because of the scarcity of studies, inter-study heterogeneity, too few outcome events, or insufficient power. An abductive inference approach, where the body of evidence is evaluated beyond considerations of statistical significance, may serve as a tool to assess the plausibility of performance-enhancing effects of substances by also considering observations and facts not solely obtained from RCTs. Herein, we explored the applicability of an abductive inference approach as a tool to assess the performance-enhancing effects of substances included on the Prohibited List. We applied an abductive inference approach to make inferences on debated issues pertaining to the ergogenic effects of recombinant human erythropoietin (rHuEPO), beta 2 -agonists and anabolic androgenic steroids (AAS), and extended the approach to more controversial drug classes where RCTs are limited. We report that an abductive inference approach is a useful tool to assess the ergogenic effect of substances included on the Prohibited List—particularly for substances where inductive inference is inconclusive. Specifically, a systematic abductive inference approach can aid researchers in assessing the effects of doping substances, either by leading to suggestions of causal relationships or identifying the need for additional research.