Real-world outcomes following third or subsequent lines of therapy: A Danish population-based study on 189 patients with relapsed/refractory large B-cell lymphomas.

Outcome data of patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) beyond the second line are scarce outside of clinical trials. Novel therapies in the R/R setting have been approved based on single-arm trials, but results need to be contextualized by real-world outcomes. Medical records from 3753 Danish adults diagnosed with DLBCL were reviewed. Patients previously treated with rituximab and anthracycline-based chemotherapy who received the third or later line (3 L+) of treatment after 1 January 2015, were included. Only 189 patients with a median age of 71 years were eligible. The median time since the last line of therapy was 6 months. Patients were treated with either best supportive care (22%), platinum-based salvage therapy (13%), low-intensity chemotherapy (22%), in clinical trial (14%) or various combination treatments (32%). The 2-year OS-/PFS estimates were 25% and 12% for all patients and 49% and 17% for those treated with platinum-based salvage therapy. Age ≥70, CNS involvement, elevated LDH and ECOG ≥2 predicted poor outcomes, and patients with 0-1 of these risk factors had a 2-year OS estimate of 65%. Only a very small fraction of DLBCL patients received third-line treatment and were eligible for inclusion. Outcomes were generally poor, but better in intensively treated, fit young patients with limited disease.

Determinants and reference values for blood volume and total hemoglobin mass in women and men.

Blood volume (BV) is an important clinical parameter and is usually reported per kg of body mass (BM). When fat mass is elevated, this underestimates BV/BM. One aim was to study if differences in BV/BM related to sex, age, and fitness would decrease if normalized to lean body mass (LBM). The analysis included 263 women and 319 men (age: 10-93 years, body mass index: 14-41 kg/m2 ) and 107 athletes who underwent assessment of BV and hemoglobin mass (Hbmass ), body composition, and cardiorespiratory fitness. BV/BM was 25% lower (70.3 ± 11.3 and 80.3 ± 10.8 mL/kgBM ) in women than men, respectively, whereas BV/LBM was 6% higher in women (110.9 ± 12.5 and 105.3 ± 11.2 mL/kgLBM ). Hbmass /BM was 34% lower (8.9 ± 1.4 and 11.5 ± 11.2 g/kgBM ) in women than in men, respectively, but only 6% lower (14.0 ± 1.5 and 14.9 ± 1.5 g/kgLBM )/LBM. Age did not affect BV. Athlete's BV/BM was 17.2% higher than non-athletes, but decreased to only 2.5% when normalized to LBM. Of the variables analyzed, LBM was the strongest predictor for BV (R2 = .72, p < .001) and Hbmass (R2 = .81, p < .001). These data may only be valid for BV/Hbmass when assessed by CO re-breathing. Hbmass /LBM could be considered a valuable clinical matrix in medical care aiming to normalize blood homeostasis.

Duplicate measures of hemoglobin mass within an hour: feasibility, reliability, and comparison of three devices in supine position.

Duplicate measure of hemoglobin mass by carbon monoxide (CO)-rebreathing is a logistical challenge as recommendations prompt several hours between measures to minimize CO-accumulation. This study investigated the feasibility and reliability of performing duplicate CO-rebreathing procedures immediately following one another. Additionally, it was evaluated whether the obtained hemoglobin mass from three different CO-rebreathing devices is comparable. Fifty-five healthy participants (22 males, 23 females) performed 222 duplicate CO-rebreathing procedures in total. Additionally, in a randomized cross-over design 10 participants completed three experimental trials, each including three CO-rebreathing procedures, with the first and second separated by 24 h and the second and third separated by 5-10 min. Each trial was separated by >48 h and conducted using either a glass-spirometer, a semi-automated electromechanical device, or a standard three-way plastic valve designed for pulmonary measurements. Hemoglobin mass was 3 ± 22 g lower (p < 0.05) at the second measure when performed immediately after the first with a typical error of 1.1%. Carboxyhemoglobin levels reached 10.9 ± 1.3%. In the randomized trial, hemoglobin mass was similar between the glass-spirometer and three-way valve, but ∼6% (∼50 g) higher for the semi-automated device. Notably, differences in hemoglobin mass were up to ∼13% (∼100 g) when device-specific recommendations for correction of CO loss to myoglobin and exhalation was followed. In conclusion, it is feasible and reliable to perform two immediate CO-rebreathing procedures. Hemoglobin mass is comparable between the glass-spirometer and the three-way plastic valve, but higher for the semi-automated device. The differences are amplified if the device-specific recommendations of CO-loss corrections are followed.

The future of incretins in the treatment of obesity and non-alcoholic fatty liver disease.

In the last few decades, glucagon-like peptide-1 receptor (GLP-1R) agonists have changed current guidelines and improved outcomes for individuals with type 2 diabetes. However, the dual glucose-dependent insulinotropic polypeptide receptor (GIPR)/GLP-1R agonist, tirzepatide, has demonstrated superior efficacy regarding improvements in HbA1c and body weight in people with type 2 diabetes. This has led to increasing scientific interest in incretin hormones and incretin interactions, and several compounds based on dual- and multi-agonists are now being investigated for the treatment of metabolic diseases. Herein, we highlight the key scientific advances in utilising incretins for the treatment of obesity and, potentially, non-alcoholic fatty liver disease (NAFLD). The development of multi-agonists with multi-organ targets may alter the natural history of these diseases.

Sustained heart rate-corrected QT prolongation during recovery from hypoglycaemia in people with type 1 diabetes, independently of recovery to hyperglycaemia or euglycaemia.

AIM: To investigate changes in cardiac repolarization abnormalities (heart rate-corrected QT [QTc ] [primary endpoint], T-wave abnormalities) and heart-rate variability measures in people with type 1 diabetes during insulin-induced hypoglycaemia followed by recovery hyperglycaemia versus euglycaemia. METHODS: In a randomized crossover study, 24 individuals with type 1 diabetes underwent two experimental clamps with three steady-state phases during electrocardiographic monitoring: (1) a 45-minute euglycaemic phase (5-8 mmol/L), (2) a 60-minute insulin-induced hypoglycaemic phase (2.5 mmol/L), and (3) 60-minute recovery in either hyperglycaemia (20 mmol/L) or euglycaemia (5-8 mmol/L). RESULTS: All measured markers of arrhythmic risk indicated increased risk during hypoglycaemia. These findings were accompanied by a decrease in vagal tone during both hyperglycaemia and euglycaemia clamps. Compared with baseline, the QTc interval increased during hypoglycaemia, and 63% of the participants exhibited a peak QTc of more than 500 ms. The prolonged QTc interval was sustained during both recovery phases with no difference between recovery hyperglycaemia versus euglycaemia. During recovery, no change from baseline was observed in heart-rate variability measures. CONCLUSIONS: In people with type 1 diabetes, insulin-induced hypoglycaemia prolongs cardiac repolarization, which is sustained during a 60-minute recovery period independently of recovery to hyperglycaemia or euglycaemia. Thus, vulnerability to serious cardiac arrhythmias and sudden cardiac death may extend beyond a hypoglycaemic event, regardless of hyperglycaemic or euglycaemic recovery.

Exercise-related hypoglycaemia induces QTc-interval prolongation in individuals with type 1 diabetes.

AIMS: To investigate changes in cardiac repolarisation during exercise-related hypoglycaemia compared to hypoglycaemia induced at rest in people with type 1 diabetes. MATERIAL AND METHODS: In a randomised crossover study, 15 men with type 1 diabetes underwent two separate hyperinsulinaemic euglycaemic-hypoglycaemic clamp experiments during Holter-ECG monitoring. One experiment included a bout of moderate-intensity cycling exercise (60 min) along with declining plasma glucose (PG; Clamp-exercise). In the other experiment, hypoglycaemia was induced with the participants at rest (Clamp-rest). We studied QTc interval, T-peak to T-end (Tpe) interval and hormonal responses during three steady-state phases: (i) baseline (PG 4.0-8.0 mmol/L); (ii) hypoglycaemic phase (PG <3.0 mmol/L); and (iii) recovery phase (PG 4.0-8.0 mmol/L). RESULTS: Both QTc interval and Tpe interval increased significantly from baseline during the hypoglycaemic phase but with no significant difference between test days. These changes were accompanied by an increase in plasma adrenaline and a decrease in plasma potassium on both days. During the recovery phase, ΔQTc interval was longer during Clamp-rest compared to Clamp-exercise, whereas ΔTpe interval remained similar on the two test days. CONCLUSIONS: We found that both exercise-related hypoglycaemia and hypoglycaemia induced at rest can cause QTc-interval prolongation and Tpe-interval prolongation in people with type 1 diabetes. Thus, both scenarios may increase susceptibility to ventricular arrhythmias.

Glycaemia and cardiac arrhythmias in people with type 1 diabetes: A prospective observational study.

AIM: To investigate the impact of hypoglycaemia, hyperglycaemia and glycaemic variability on arrhythmia susceptibility in people with type 1 diabetes. MATERIALS AND METHODS: Thirty adults with type 1 diabetes were included in a 12-month observational exploratory study. Daytime and night-time incident rate ratios (IRRs) of arrhythmias were determined for hypoglycaemia (interstitial glucose [IG] <3.9 mmol/L), hyperglycaemia (IG >10.0 mmol/L) and glycaemic variability (standard deviation and coefficient of variation). RESULTS: Hypoglycaemia was not associated with an increased risk of arrhythmias compared with euglycaemia and hyperglycaemia combined (IG ≥ 3.9 mmol/L). However, during daytime, a trend of increased risk of arrhythmias was observed when comparing time spent in hypoglycaemia with euglycaemia (IRR 1.08 [95% CI: 0.99-1.18] per 5 minutes). Furthermore, during daytime, both the occurrence and time spent in hyperglycaemia were associated with an increased risk of arrhythmias compared with euglycaemia (IRR 2.03 [95% CI: 1.21-3.40] and IRR 1.07 [95% CI: 1.02-1.13] per 5 minutes, respectively). Night-time hypoglycaemia and hyperglycaemia were not associated with the risk of arrhythmias. Increased glycaemic variability was not associated with an increased risk of arrhythmias during daytime, whereas a reduced risk was observed during night-time. CONCLUSIONS: Acute hypoglycaemia and hyperglycaemia during daytime may increase the risk of arrhythmias in individuals with type 1 diabetes. However, no such associations were found during night-time, indicating diurnal differences in arrhythmia susceptibility.

Moderate hypoxic exposure for 4 weeks reduces body fat percentage and increases fat-free mass in trained individuals: a randomized crossover study.

PURPOSE: We evaluated whether or not changes in body composition following moderate hypoxic exposure for 4 weeks were different compared to sea level exposure. METHODS: In a randomized crossover design, nine trained participants were exposed to 2320 m of altitude or sea level for 4 weeks, separated by > 3 months. Body fat percentage (BF%), fat mass (FM), and fat-free mass (FFM) were determined before and after each condition by dual X-ray absorptiometry (DXA) and weekly by a bioelectrical impedance scanner to determine changes with a high resolution. Training volume was quantified during both interventions. RESULTS: Hypoxic exposure reduced (P < 0.01) BF% by 2 ± 1 percentage points and increased (P < 0.01) FFM by 2 ± 2% determined by DXA. A tending time × treatment effect existed for FM determined by DXA (P = 0.06), indicating a reduced FM in hypoxia by 8 ± 7% (P < 0.01). Regional body analysis revealed reduced (P < 0.01) BF% and FFM and an increased (P < 0.01) FFM in the truncus area. No changes were observed following sea level. Bioelectrical impedance determined that BF%, FM, and FFM did not reveal any differences between interventions. Urine specific gravity measured simultaneously as body composition was identical. Training volume was similar between interventions (509 ± 70 min/week vs. 432 ± 70 min/week, respectively). CONCLUSIONS: Four weeks of altitude exposure reduced BF% and increased FFM in trained individuals as opposed to sea level exposure. The results also indicate that a decrease in FM is greater at altitude compared to sea level. Changes were specifically observed in the truncus area.

Robust arm and leg muscle adaptation to training despite ACE inhibition: a randomized placebo-controlled trial.

PURPOSE: Angiotensin-converting enzyme (ACE) inhibitor treatment is widely applied, but the fact that plasma ACE activity is a potential determinant of training-induced local muscular adaptability is often neglected. Thus, we investigated the hypothesis that ACE inhibition modulates the response to systematic aerobic exercise training on leg and arm muscular adaptations. METHODS: Healthy, untrained, middle-aged participants (40 ± 7 yrs) completed a randomized, double-blinded, placebo-controlled trial. Participants were randomized to placebo (PLA: CaCO3) or ACE inhibitor (ACEi: enalapril) for 8 weeks and completed a supervised, high-intensity exercise training program. Muscular characteristics in the leg and arm were extensively evaluated pre and post-intervention. RESULTS: Forty-eight participants (nACEi = 23, nPLA = 25) completed the trial. Exercise training compliance was above 99%. After training, citrate synthase, 3-hydroxyacyl-CoA dehydrogenase and phosphofructokinase maximal activity were increased in m. vastus lateralis in both groups (all P < 0.05) without statistical differences between them (all time × treatment P > 0.05). In m. deltoideus, citrate synthase maximal activity was upregulated to a greater extent (time × treatment P < 0.05) in PLA (51 [33;69] %) than in ACEi (28 [13;43] %), but the change in 3-hydroxyacyl-CoA dehydrogenase and phosphofructokinase maximal activity was similar between groups. Finally, the training-induced changes in the platelet endothelial cell adhesion molecule-1 protein abundance, a marker of capillary density, were similar in both groups in m. vastus lateralis and m. deltoideus. CONCLUSION: Eight weeks of high-intensity whole-body exercise training improves markers of skeletal muscle mitochondrial oxidative capacity, glycolytic capacity and angiogenesis, with no overall effect of pharmacological ACE inhibition in healthy adults.

Validation of a clinically applicable device for fast and accurate quantification of blood volume.

INTRODUCTION: Determination of blood volume (BV) using the dual-isotope (e.g., 99m Tc-labeled red blood cells [99m Tc-RBC] and 125 I-labeled human serum albumin [125 I-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.

A semi-automated device rapidly determine circulating blood volume in healthy males and carbon monoxide uptake kinetics of arterial and venous blood.

We examined whether a semi-automated carbon monoxide (CO) rebreathing method accurately detect changes in blood volume (BV) and total hemoglobin mass (tHb). Furthermore, we investigated whether a supine position with legs raised reduced systemic CO dilution time, potentially allowing a shorter rebreathing period. Nineteen young healthy males participated. BV and tHb was quantified by a 10-min CO-rebreathing period in a supine position with legs raised before and immediately after a 900 ml phlebotomy and before and after a 900 ml autologous blood reinfusion on the same day in 16 subjects. During the first CO-rebreathing, arterial and venous blood samples were drawn every 2 min during the procedure to determine systemic CO equilibrium in all subjects. Phlebotomy decreased (P < 0.001) tHb and BV by 166 ± 24 g and 931 ± 247 ml, respectively, while reinfusion increased (P < 0.001) tHb and BV by 143 ± 21 g and 862 ± 250 ml compared to before reinfusion. After reinfusion BV did not differ from baseline levels while tHb was decreased (P < 0.001) by 36 ± 21 g. Complete CO mixing was achieved within 6 min in venous and arterial blood, respectively, when compared to the 10-min sample. On an individual level, the relative accuracy after donation for tHb and BV was 102-169% and 55-165%, respectively. The applied CO-rebreathing procedure precisely detect acute BV changes with a clinically insignificant margin of error. The 10-min CO-procedure may be reduced to 6 min with no clinical effects on BV and tHb calculation. Notwithstanding, individual differences may be of concern and should be investigated further.

Hypoglycaemia and rebound hyperglycaemia increase left ventricular systolic function in patients with type 1 diabetes.

AIM: To investigate echocardiographic changes during acute hypoglycaemia followed by recovery to hyperglycaemia or euglycaemia in patients with type 1 diabetes. MATERIALS AND METHODS: In a randomized crossover study, 24 patients with type 1 diabetes took part in two experimental study days, consisting of a hyperinsulinaemic-euglycaemic phase (5.0-8.0 mmol/L) for 45 minutes followed by a hyperinsulinemic-hypoglycaemic phase (2.5 mmol/L) for 60 minutes, and a recovery phase in either hyperglycaemia (20 mmol/L) or euglycaemia (5.0-8.0 mmol/L) for 60 minutes. Cardiac function was evaluated with echocardiography during each phase. RESULTS: Acute hypoglycaemia increased all markers of left ventricular (LV) systolic function, including LV ejection fraction (LVEF), global longitudinal strain (GLS), GLS rate and peak systolic velocity of mitral annular longitudinal movement (s'; P < 0.001 for all). During the recovery phases, all markers of LV systolic function were increased during hyperglycaemia (P < 0.01 for all), and LVEF and GLS remained increased during euglycaemia (P = 0.0116 and P = 0.0092, respectively). The increment in LVEF during the recovery phase was greater during hyperglycaemia than euglycaemia (P = 0.0046). CONCLUSIONS: Hypoglycaemia, recent hypoglycaemia, and overcorrection of hypoglycaemia to rebound hyperglycaemia increased LV systolic function in type 1 diabetes and may imply consideration of plasma glucose when evaluating LV function in patients with type 1 diabetes. An increase in LV systolic function may cause increased strain on the heart and partly explain the link between hypoglycaemia, high glycaemic variability and cardiovascular disease.

Acute changes in plasma glucose increases left ventricular systolic function in insulin-treated patients with type 2 diabetes and controls.

AIMS: We aimed to evaluate the effect of acute hyperglycaemia and hypoglycaemia on cardiac function in patients with type 2 diabetes (T2D) and a control group. MATERIALS AND METHODS: In a nonrandomized interventional study, insulin-treated patients with T2D (N = 21, mean ± SD age 62.8 ± 6.5 years, body mass index [BMI] 29.0 ± 4.2 kg/m2 , glycated haemoglobin [HbA1c] 51.0 ± 5.4 mmol/mol [6.8 ± 0.5%]) and matched controls (N = 21, mean ± SD age 62.2 ± 8.3 years, BMI 29.2 ± 3.5 kg/m2 , HbA1c 34.3 ± 3.3 mmol/L [5.3 ± 0.3%]) underwent one experimental day with plasma glucose (PG) clamped at three different 30-minute steady-state levels: (1) fasting plasma glucose (FPG); (2) hyperglycaemia (FPG + 10 mmol/L); and (3) hyperinsulinaemic hypoglycaemia (PG <3.0 mmol/L). Cardiac function was evaluated during each steady state by echocardiography. RESULTS: Acute hyperglycaemia increased left ventricular (LV) ejection fraction from baseline in patients with T2D (mean [95% confidence interval] 4.5 percentage points [1.1; 7.9]) but not in controls (2.0 percentage points [-1.4; 5.4]). Mitral annular peak systolic velocity (s') increased during hyperglycaemia in both patients and controls (0.4 m/s [0.2;0.6] and 0.6 m/s [0.4; 0.8], respectively), whereas global longitudinal strain rate only increased in the controls (-0.05 s-1 [-0.12; 0.02] and -0.11 s-1 [-0.18; -0.03], respectively). All measures of LV systolic function increased markedly during hypoglycaemia (P <0.01 for all). No interaction between group and PG level on cardiac function was observed. CONCLUSIONS: Acute hyperglycaemia and hypoglycaemia increase LV systolic function, with no difference between patients with T2D and controls. Standardization of PG may improve reproducibility when evaluating LV systolic function in patients with T2D.

Contemporary blood doping-Performance, mechanism, and detection.

Blood doping is prohibited for athletes but has been a well-described practice within endurance sports throughout the years. With improved direct and indirect detection methods, the practice has allegedly moved towards micro-dosing, that is, reducing the blood doping regime amplitude. This narrative review evaluates whether blood doping, specifically recombinant human erythropoietin (rhEpo) treatment and blood transfusions are performance-enhancing, the responsible mechanism as well as detection possibilities with a special emphasis on micro-dosing. In general, studies evaluating micro-doses of blood doping are limited. However, in randomized, double-blinded, placebo-controlled trials, three studies find that infusing as little as 130 ml red blood cells or injecting 9 IU × kg bw-1 rhEpo three times per week for 4 weeks improve endurance performance ~4%-6%. The responsible mechanism for a performance-enhancing effect following rhEpo or blood transfusions appear to be increased O2 -carrying capacity, which is accompanied by an increased muscular O2 extraction and likely increased blood flow to the working muscles, enabling the ability to sustain a higher exercise intensity for a given period. Blood doping in micro-doses challenges indirect detection by the Athlete Biological Passport, albeit it can identify ~20%-60% of the individuals depending on the sample timing. However, novel biomarkers are emerging, and some may provide additive value for detection of micro blood doping such as the immature reticulocytes or the iron regulatory hormones hepcidin and erythroferrone. Future studies should attempt to validate these biomarkers for implementation in real-world anti-doping efforts and continue the biomarker discovery.

Out-of-Sequence Vaccinations With Measles Vaccine and Diphtheria-Tetanus-Pertussis Vaccine: A Reanalysis of Demographic Surveillance Data From Rural Bangladesh.

BACKGROUND: Due to delays in vaccinations, diphtheria-tetanus-whole-cell-pertussis (DTP) is often given with or after measles vaccine (MV)-out of sequence. We reanalyzed data from Matlab, Bangladesh, to examine how administration of MV and DTP out-of-sequence was associated with child survival. METHODS: In sum, 36 650 children born between 1986 and 1999 were followed with registration of vaccinations and survival. Controlling for background factors using Cox proportional hazards models, survival was analyzed between 9 and 24 months of age. We measured the mortality rate ratio (MRR) to compare vaccination groups. Oral polio vaccine (OPV) campaigns, which started in 1995, reduced the mortality rate and reduced the difference between vaccination groups. In the main analysis, we therefore censored for OPV campaigns; there were 151 nonaccident deaths before the OPV campaigns. RESULTS: Compared with MV administered alone (MV-only), DTP administered with or after MV had MRR 2.20 (1.31-3.70), and DTP-only had MRR 1.78 (1.01-3.11). Compared with MV-only, DTP administered with MV had a female-male MRR 0.56 (0.13-2.38), significantly different to DTP administered after MV, which had MRR 14.83 (1.88-117.1), test of interaction P = .011. Compared with having DTP (no MV) as most recent vaccination, MV-only had a nonaccident MRR of 0.56 (0.32-0.99). CONCLUSION: The negative effects of non-live DTP with or after live MV are not explained merely by selection bias. These observations support a live-vaccine-last policy where DTP should not be given with or after MV.

National Immunization Campaigns With Oral Polio Vaccine May Reduce All-cause Mortality: An Analysis of 13 Years of Demographic Surveillance Data From an Urban African Area.

BACKGROUND: Between 2002 and 2014, Guinea-Bissau had 17 national campaigns with oral polio vaccine (OPV) as well as campaigns with vitamin A supplementation (VAS), measles vaccine (MV), and H1N1 influenza vaccine. We examined the impact of these campaigns on child survival. METHODS: We examined the mortality rate between 1 day and 3 years of age of all children in the study area. We used Cox models with age as underlying time to calculate adjusted mortality rate ratios (MRRs) between "after-campaign" mortality and "before-campaign" mortality, adjusted for temporal change in mortality and stratified for season at risk. RESULTS: Mortality was lower after OPV-only campaigns than before, with an MRR for after-campaign vs before-campaign being 0.75 (95% confidence interval [CI], .67-.85). Other campaigns did not have similar effects, the MRR being 1.22 (95% CI, 1.04-1.44) for OPV + VAS campaigns, 1.39 (95% CI, 1.20-1.61) for VAS-only campaigns, 1.32 (95% CI, 1.09-1.60) for MV + VAS campaigns, and 1.13 (95% CI, .86-1.49) for the H1N1 campaign. Thus, all other campaigns differed significantly from the effect of OPV-only campaigns. Effects did not differ for trivalent, bivalent, or monovalent strains of OPV. With each additional campaign of OPV only, the mortality rate declined further (MRR, 0.86 [95% CI, .81-.92] per campaign). With follow-up to 3 years of age, the number needed to treat to save 1 life with the OPV-only campaign was 50 neonates. CONCLUSIONS: OPV campaigns can have a much larger effect on child survival than otherwise assumed. Stopping OPV campaigns in low-income countries as part of the endgame for polio infection may increase child mortality.

Effects of altitude and recombinant human erythropoietin on iron metabolism: a randomized controlled trial.

Current markers of iron deficiency (ID), such as ferritin and hemoglobin, have shortcomings, and hepcidin and erythroferrone (ERFE) could be of clinical relevance in relation to early assessment of ID. Here, we evaluate whether exposure to altitude-induced hypoxia (2,320 m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a 4-wk baseline, a 4-wk intervention at either sea level or altitude, and a 4-wk follow-up. Participants (n = 39) were randomly assigned to 20 IU·kg body wt-1 rHuEPO or placebo injections every second day for 3 wk during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE (P ≤ 0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE (P < 0.05) and hepcidin levels (P < 0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared with altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin (P < 0.05) and ERFE (P ≤ 0.001) parallel with increases in hematocrit (P < 0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found (R2 = 0.13, P < 0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an antidoping context.

Associations of hypoglycemia, glycemic variability and risk of cardiac arrhythmias in insulin-treated patients with type 2 diabetes: a prospective, observational study.

BACKGROUND: Insulin-treated patients with type 2 diabetes (T2D) are at risk of hypoglycemia, which is associated with an increased risk of cardiovascular disease and mortality. Using a long-term monitoring approach, we investigated the association between episodes of hypoglycemia, glycemic variability and cardiac arrhythmias in a real-life setting. METHODS: Insulin-treated patients with T2D (N = 21, [mean ± SD] age 66.8 ± 9.6 years, BMI 30.1 ± 4.5 kg/m2, HbA1c 6.8 ± 0.4% [51.0 ± 4.8 mmol/mol]) were included for a one-year observational study. Patients were monitored with continuous glucose monitoring ([mean ± SD] 118 ± 6 days) and an implantable cardiac monitor (ICM) during the study period. RESULTS: Time spend in hypoglycemia was higher during nighttime than during daytime ([median and interquartile range] 0.7% [0.7-2.7] vs. 0.4% [0.2-0.8]). The ICMs detected 724 episodes of potentially clinically significant arrhythmias in 12 (57%) participants, with atrial fibrillation and pauses accounting for 99% of the episodes. No association between hypoglycemia and cardiac arrhythmia was found during daytime. During nighttime, subject-specific hourly incidence of cardiac arrhythmias tended to increase with the occurrence of hypoglycemia (incident rate ratio [IRR] 1.70 [95% CI 0.36-8.01]) but only slightly with increasing time in hypoglycemia (IRR 1.04 [95% CI 0.89-1.22] per 5 min). Subject-specific incidence of cardiac arrhythmias during nighttime increased with increasing glycemic variability as estimated by coefficient of variation whereas it decreased during daytime (IRR 1.33 [95% CI 1.05-1.67] and IRR 0.77 [95% CI 0.59-0.99] per 5% absolute increase, respectively). CONCLUSIONS: Cardiac arrhythmias were common in insulin-treated patients with T2D and were associated with glycemic variability, whereas arrhythmias were not strongly associated with hypoglycemia. TRIAL REGISTRATION: NCT03150030, ClinicalTrials.gov, registered May 11, 2017. https://clinicaltrials.gov/ct2/show/NCT03150030.

Understanding the place for GLP-1RA therapy: Translating guidelines for treatment of type 2 diabetes into everyday clinical practice and patient selection.

Since the first glucagon-like peptide 1 (GLP-1) receptor agonist (GLP-1RA) was approved in 2005 (exenatide twice daily) for type 2 diabetes (T2D), the class has developed with newer compounds having more pronounced effects on glycaemic control and body weight. Also, administration regimes have become more convenient with once weekly injections, and recently an oral administration has become available. Large-scale randomized controlled cardiovascular (CV) outcome trials (CVOTs) have shown that GLP-1RA therapy can reduce the risk of CV disease (CVD) in high-risk individuals with T2D. In addition, GLP-1RAs may have renal benefits driven by new-onset macroalbuminuria, although no effect on hard renal endpoints has been found. Subsequently, the place for GLP-1RA therapy has changed over recent years, with most societies endorsing GLP-1RA therapy in patients with established or high risk of CVD independently of glycaemia. Initiation of GLP-1RA therapy can be complex due to differences in efficacy, side effects and safety profiles as well as administration forms within the class. Implementing guideline recommendations into ideal patient selection may be challenging both in specialty and non-specialty settings. To ensure adequate and proactive use of modern glucose-lowering medications in the treatment of T2D, it is essential to recognize patients with high risk or documented CVD. The present review provides an overview of the efficacy and benefits of the currently available GLP-1RA compounds. Furthermore, we review the results from recent large-scale CVOTs in a clinical context and suggest improving the implementation of GLP-1RA therapy across specialties to improve overall patient selection.

Comparison of the injection-site experience of the starting doses with semaglutide and dulaglutide: A randomized, double-blind trial in healthy subjects.

This double-blind, randomized, single-site, crossover trial compared the injection-site experience with the starting doses of semaglutide and dulaglutide. Healthy subjects (aged 18-75 years; body mass index ≥ 25 kg/m2 ; n = 104) were randomized 1:1, using a pregenerated list, to semaglutide 0.25 mg as the first injection and dulaglutide 0.75 mg as the second injection or vice versa; each was administered using their proprietary pen-injectors, according to instructions for use. The primary endpoint was intensity of injection-site pain, measured using a visual analogue scale (VAS; 0 mm = no pain, 100 mm = unbearable pain). Exploratory endpoints included intensity category, duration and quality of injection-site pain, and comparative assessment of injection-site pain with the two injections. The point estimate of the VAS score for injection-site pain intensity was 11.5 mm with dulaglutide versus 5.6 mm with semaglutide; mean (95% confidence interval) estimated treatment difference 5.9 (3.6; 8.2) mm; p < .0001. Other endpoints corroborated a less painful injection experience with semaglutide versus dulaglutide. Safety was consistent with reported data for the drugs. In conclusion, the injection-site experience with semaglutide was rated as less painful than that with dulaglutide.