Metabolic control level and glucose variability in adolescents with type 1 diabetes during low and high-intensity exercise.

OBJECTIVE: The main purpose of this study was to characterize the determinants of metabolic changes in young type 1 diabetes (T1DM) and to determine glycemic variability during low and high-intensity exercise. PATIENTS AND METHODS: 20 young male T1DM patients were divided into two subgroups characterized by levels of glycated hemoglobin (HbA1c): HbA1c<7.3% (better HbA1c subgroup, n=10) and with levels HbA1c>7.3% (worse HbA1c subgroup, n=10). All participants performed a maximal oxygen uptake test and two efforts of various intensities (45 minutes of aerobic exercise and 30 minutes of mixed aerobic-anaerobic intensity exercise). Continuous glucose monitors (CGM) were used to control the glucose concentration. RESULTS: Changes in biomarkers describing the metabolic response were similar in both groups. A comparison of applied efforts exhibited that maximal capacity effort resulted in the highest values of blood glucose (BG) at the end (150.9-160.6 mg/dl) and 1 hour after the exercise (140.2-161.3 mg/dl). BG concentration before, during, 1 hour, and 24 hours after each exercise was insignificantly higher in the worse Hb1Ac group. CONCLUSIONS: HbA1c levels are insufficient to confirm whether the applied effort is performed in acceptable glycemic values. The CGM monitors allow for precise control of BG variations and accurate planning of physical activity by adjusting the insulin and carbohydrate consumption dose.

Effects of moderate- vs. high-intensity interval training on physical fitness, enjoyment, and affective valence in overweight/obese female adolescents: a pre-/post-test study.

OBJECTIVE: The aim of this study was to compare the effects of 12-week moderate-intensity interval training (MIIT) vs. high-intensity interval training (HIIT) on body composition, physical fitness, and psychological valence in overweight/obese (OW/OB) female adolescents. PATIENTS AND METHODS: Thirty-eight OW/OB female students were randomized into HIIT (n=13), MIIT (n=13) or control (n=12) groups. The participants underwent a 12-week interval-training program at 100% to 110% and 60% to 75% of maximal aerobic speed for HIIT and MIIT, respectively. The control group kept their usual physical activity without completing the training program. Pre- and post-training measurements were performed to assess body composition, aerobic capacity, and anaerobic performance (using selected tests evaluating speed, jumping ability, and strength). Ratings of perceived exertion and the feeling scale were evaluated every three weeks. Enjoyment was measured at the end of the program. A two-way analysis of variance with repeated measurements was applied to test for "group×time" interactions for body composition, physical fitness, and affective variables. RESULTS: Significant "group×time" interactions were detected for aerobic and anaerobic performance, body composition indices, and the feeling scale. HIIT resulted in more noticeable improvements in body composition and physical performance than MIIT, while no significant changes were found in the control group. Throughout the program, the feeling score has progressively increased in the MIIT group but decreased in the HIIT group. Ratings of the perceived exertion have increased in both groups, more noticeably in the HIIT group. At the end of the program, the MIIT group showed a higher enjoyment score. CONCLUSIONS: Despite offering better body composition improvement and physical fitness enhancement, HIIT offered lesser enjoyment and affective valence than MIIT in OW/OB female adolescents. MIIT might be an alternative time-efficient protocol for improving health in this population.

Skinfold thickness variation and associations with cardiorespiratory fitness in male soccer players of different ages.

OBJECTIVE: The aim of the present study was to examine skinfold thickness (SKF) distribution in youth and adult male soccer players regarding cardiorespiratory fitness (CRF) and the role of age. PATIENTS AND METHODS: Participants were youth [n=83, age 16.2 (1.0) years, mean (standard deviation)] and adult male soccer players [n=121, 23.2 (4.3) years], who were tested for SKF on 10 anatomical sites and Conconi test was used to assess velocity at maximal oxygen uptake (vVO2max). RESULTS: A between-within-subjects analysis of variance revealed a small interaction between the anatomical site and age group on SKF (p=0.006, η2=0.022), where adolescents had larger cheek (+0.7 mm; p=0.022; 95% confidence intervals - CI  - 0.1, 1.3), triceps (+0.9 mm; p=0.017; 95% CI 0.2, 1.6) and calf (+0.9 mm; p=0.014; 95% CI 0.2, 1.5) SKF, while adults had larger chin (+0.5 mm; p=0.007; 95% CI 0.1, 0.8) SKF, and no difference was observed for the rest of the anatomical sites. No difference between adolescent and adult age groups was observed in average SKF (SKFavg) [9.0 (2.7) vs. 9.1 (2.5) mm; difference -0.1 mm; 95% CI, -0.8, 0.6; p=0.738]. Compared to adults, adolescents had a lower SKF coefficient of variation (SKFcv) [0.34 (0.10) vs. 0.37 (0.09); difference-0.03; 95% CI, -0.06, -0.01; p=0.020] and subscapular-to-triceps ration (STR) [1.08 (0.28) vs. 1.29 (0.37); difference-0.21; 95% CI, -0.31, -0.12; p<0.001]. The largest Pearson moment correlation coefficient between vVO2max and SKF was shown in the subscapular (r=-0.411; 95% CI, -0.537, -0.284; p<0.001) and the smallest in the patellar anatomical site (r=-0.221; 95% CI, -0.356, -0.085; p=0.002). In addition, vVO2max correlated moderately with SKFavg (r=-0.390; 95% CI, -0.517, -0.262; p<0.001) and SKFcv (r=-0.334; 95% CI, -0.464, -0.203; p<0.001). CONCLUSIONS: In summary, CRF was related to the thickness of specific SKF and the magnitude of thickness variation by the anatomical site (i.e., the smaller the variation, the better the CRF). Considering the relevance of specific SKF for CRF, their further use would be recommended for monitoring physical fitness in soccer players.

How to end up on the podium after running a 6-days-run with type 1 diabetes mellitus - A case study and literature review.

BACKGROUND: An increasing number of people living with type 1 diabetes mellitus (T1DM) are pushing their physical limits to compete at the sport's highest level. Muscle, liver, and glycogen metabolism can be normal in athletes with diabetes with good glucose management, and modifications to insulin dose and nutrition can facilitate exercise performance. CASE PRESENTATION: We report on a 66-year-old runner with insulin-dependent T1DM. He has run over 90 marathons and ultra-marathons. Thanks to an insulin pump and continuous glucose monitoring, he has completed forty-eight 24-hour runs with an average performance of 133.8 km. Over the years, the runner increased his monthly running volume significantly and decreased his glycated Hemoglobin type A1C (hba1c) levels. Meanwhile, a significant association between monthly running kilometers and hba1c levels could be shown. At the age of 66 years, he finished his sixth 6-day-run in third place overall by covering a total distance of 467.424 km. CONCLUSIONS: These findings show that it is possible to participate in ultra-endurance events while suffering from T1DM without glucose derailing. With a good understanding of the disease and its impact on an individual's body, we can curtail the preparation and execution phases of ultra-endurance events to allow athletes to compete with minimal risk.

Performance improvement in sport through vitamin D - a narrative review.

OBJECTIVE: It is well known that vitamin D deficiency can lead to various health problems. However, it is not common knowledge among athletes and doctors that vitamin D deficiency is prevalent in sports. This deficiency can severely impact performance, while vitamin D supplementation can alleviate this effect and potentially improve performance. MATERIALS AND METHODS: This narrative review aims to compile the current state of knowledge about the importance of vitamin D in increasing performance for active people. To this end, we searched the 'Scopus' and 'PubMed' databases for the terms 'vitamin D - athlete - performance' with an end date of 30 June 2022. RESULTS: Study results indicated that the therapeutic impact of vitamin D on aerobic capacity, recovery, strength and sprint performance remains controversial. CONCLUSIONS: Based on the previous findings on recovery, strength and performance, 4,000-5,000 IU of vitamin D per day may be a safe dose that can improve athletic performance.

The effects of cognitive behavioral therapy on selected physical, physiological parameters, exercise and nutritional behaviors in diabetic persons.

OBJECTIVE: Due to the high prevalence of diabetes in the world, it seems that one of the most important strategies to prevent and treat this disease are lifestyle changes. The present study aimed to investigate the effects of cognitive behavioral therapy on selected physical and psychological parameters, exercise, and nutritional behaviors in diabetic patients. PATIENTS AND METHODS: This was a cross-sectional study of volunteers with type 2 diabetes. Patients were randomized into two groups: an intervention (n=32) and a control group (n=31). The Beck Physical Activity Questionnaire was used to assess physical activity in combination with the Beck Depression Inventory and the Pittsburgh Sleep Quality Index to assess the levels of depression and the quality of sleep. Cognitive behavior therapy (CBT) training consisted of six sessions of cognitive behavioral therapy interventions. The intervention consisted of a face-to-face individual counseling session. The patients received a special diet according to their basal metabolic rate (BMR). At all sessions, dietary advice was reviewed, and during the treatment period, they were asked to record their diet and physical activity. Body composition and blood samples were measured before and after three months of the experiment for both groups. RESULTS: Blood glucose, blood lipid profiles (except high-density lipoprotein), lifestyle, behavior patterns and body composition were significantly improved following CBT intervention (p≤0.05). CONCLUSIONS: CBT can play a key role in improving physiological and psychological parameters in diabetic patients.

Autoimmune hepatitis in monozygotic twins - a case report.

OBJECTIVE: Autoimmune hepatitis is a chronic liver disease caused by a dysfunctional immune system. It is widely believed that autoimmune hepatitis accumulates in families. We found that autoimmune hepatitis does accumulate in monozygotic twins. CASE REPORT: We present middle-aged monozygotic female twins developing autoimmune hepatitis consecutively within two years. Both twins had developed Graves' disease and were treated with carbimazole before the onset of autoimmune hepatitis. Both were cigarette smokers. The twins were treated with budesonide and azathioprine, which normalised liver parameters. CONCLUSIONS: This case report supports the hypothesis that a genetic factor might be of great importance in the aetiology of autoimmune hepatitis.

Factors associated with perceived performance drops and musculoskeletal injuries in Brazilian recreational triathletes.

OBJECTIVE: The aim of the study was to investigate sleep characteristics, use of supplements, and training volume of recreational triathletes, and to verify possible associations with perceived performance drops and occurrence of injuries. MATERIALS AND METHODS: Recreational triathletes (n=942) answered a questionnaire inquiring about their demographic characteristics, performance, injuries and training volume. RESULTS: When comparing athletes who slept more (9-10 hours) with those who slept less, less sleep was associated with a higher prevalence of perceived performance drops. Regarding difficulties in initiating sleep, the absence of initiating difficulties (p<0.001) was a protective factor against perceived performance drops. Regarding weekly training volume, compared to those who trained more than 20 hours, training less than 3 hours (p<0.001), 3-5 hours (p<0.001), or 12-14 hours (p<0.001) were protective factors against perceived performance drops. Concerning training volume and injuries, we found that compared to those who trained more than 20 hours, training 18-20 hours (p<0.001), 15-17 hours (p<0.001), 12-14 hours (p<0.001), 6-8 hours (p<0.001), or 3-5 hours (p<0.001) were protective factors against injuries. CONCLUSIONS: Triathletes with a lower sleep quantity and those who have difficulties initiating sleep frequently experience drops in performance. Training volumes can influence both performance and the likelihood of injuries.

The effects of daytime melatonin ingestion on arousal and vigilance vanish after sub-maximal exercise: a pilot study.

OBJECTIVE: Daytime melatonin ingestion is known to induce sleep at rest, which may affect arousal and vigilance. Physical exercise is known to produce an increase in core temperature and circulating cortisol which can enhance arousal and vigilance. The effect of submaximal exercise on vigilance and arousal following acute melatonin ingestion has not yet been studied. The present study aimed at investigating the effect of submaximal exercise on vigilance and arousal following daytime melatonin ingestion. PATIENTS AND METHODS: Eight physical education students undertook 45 min of submaximal exercise (at 60% of maximal aerobic speed) on a treadmill after melatonin-(6 mg) or placebo ingestion, in a randomized and counterbalanced order. RESULTS: Heart rate (HR), rectal temperature (Tre), felt arousal scale (FAS), and thermal sensations (TS) were recorded at baseline (pre-exercise), immediately after exercise (post-exercise), and after 30 min of recovery (30 min post-exercise). Blood was sampled for lactate and cortisol. At 30 min post-exercise, the Tre, HR, blood pressure, lactate, FAS, and TS were measured. The participants performed vigilance tests pre-exercise, post-exercise and 30 min post-exercise. Daytime melatonin ingestion affected arousal and vigilance in the pre-exercise period (p < 0.05) but had no effect on Tre, HR, blood pressure, lactate, TS, arousal, and vigilance measured 30 min post-exercise (p > 0.05). CONCLUSIONS: The negative effects of melatonin ingestion on vigilance and arousal vanished after a 45 min of submaximal exercise. The hypnotic effect of melatonin observed in the pre-exercise dissipated in the post-exercise period, possibly due to the significant elevation of Tre, HR, and cortisol at the end of submaximal exercise.

Differences in pacing during cycling and running in ultra-triathlons - The example of 'Swissultra'.

OBJECTIVE: The knowledge of the most predictive split discipline and the pacing during a triathlon race is of utmost importance for planning an ultra-triathlon race. This study aimed at investigating the pacing during cycling and running splits in three different multi-stage ultra-triathlon race formats (i.e., Quintuple, Deca, and Double Deca Iron ultra-triathlon with 5x, 10x and 20x the daily distance of a full Ironman-distance triathlon). SUBJECTS AND METHODS: A total of 48 male ultra-triathletes competing in Quintuple (n=14), Deca (n=25), and Double Deca (n=9) Iron ultra-triathlon "swissultra" between 2016 and 2019 in Switzerland were analyzed. For each race day, we calculated the total performance (sum of all laps time), average individual performance (average of all laps time within a race day) and pacing variation (coefficient of variation of race laps time) for cycling and running. Discipline (cycling and running) and race distance (Quintuple, Deca, and Double Deca Iron ultra-triathlon) were used as independent parameters. The primary outcome variables were the time performance (daily and total) and the pacing variation. We applied two general linear models (GLM): the first model was a one-way ANOVA comparing total and daily performance by race distance, and the second model was a two-way ANOVA (race distance´ discipline) using pacing variation (average pace oscillation) as a dependent variable. RESULTS: The first GLM identified a significant race distance effect for total performance in both cycling (F = 375.6; p < 0.001; ηp2 = 0.943) and running (F = 267.8; p < 0.001; ηp2 = 0.922) with Double Deca Iron ultra-triathlon being the fastest and Quintuple Iron ultra-triathlon the slowest. The GLM for daily average performance showed no significant effect of race distance on cycling performance (F = 0.171; p = 0.843; ηp2 = 0.008), but on running performance (F = 6.408; p = 0.004; ηp2 = 0.222). The two-way GLM comparing pacing variation showed a significant effect for race distance (F = 11.81; p<0.001; ηp2 = 0.344) with Deca presenting larger pace variation than Quintuple and Double Deca Iron ultra-triathlon in both cycling and running, but not for discipline (F = 0.067; p=0.797; ηp2 = 0.001), nor for interaction (F = 1.469; p=0.241; ηp2 = 0.061). CONCLUSIONS: Athletes achieved a stable cycling performance independent of the length of the race, and the cycling split had an influence on the subsequent running split depending upon the length of the race.

Temperature and barometric pressure are related to running speed and pacing of the fastest runners in the 'Berlin Marathon'.

OBJECTIVE: The influence of environmental conditions, such as temperature, barometric pressure, humidity, precipitation, sunshine and cloud cover on marathon running has been widely investigated. However, the influence of such conditions on the pacing of elite marathoners has not been considered yet. The present study aimed to investigate whether environmental conditions are related to the running speed and pacing of the fastest marathoners competing in the fastest racecourse in the world, the 'Berlin Marathon'. SUBJECTS AND METHODS: A total of 668,735 finishers (520,715 men and 148,020 women) competing between 1999 and 2019 in the 'Berlin Marathon' were analyzed by comparing elite and recreational runners. The associations between time-adjusted averages of the environmental conditions, the race times and running speeds were investigated. The runners were divided into performance groups consisting of recreational (all runners) and elite runners (the top 100, the top 10 and the top 3) which were separately analyzed for male and female participants. RESULTS: During race days, the temperature increased while humidity decreased showing a strong negative correlation between the two variables. For all runners, the average running speed through the race showed a strong negative correlation with temperature and a strong positive correlation with the level of humidity. Faster runners experienced lower temperatures and higher humidity levels than slower runners. When the performance groups were analyzed, temperature and humidity remained correlated to a similar extent for the top 100 but dropped dramatically for the top 10 and top 3, suggesting a weaker influence. In addition, barometric pressure showed a positive correlation with running speed in the top 100 and top 3 groups. CONCLUSIONS: Temperatures increased during race days while humidity decreased and both variables were negatively and significantly correlated. Faster runners experienced lower temperatures and higher humidity levels, while slower runners experienced higher temperatures and lower humidity levels which had a stronger negative impact on running speeds. Running speed was also significantly and positively correlated with barometric pressure in elite runners.

Comparison of the levels of depression and anxiety during the first and fourth waves of coronavirus disease-2019 pandemic in Brazil.

OBJECTIVE: To compare the levels of depression, anxiety, physical activity, and mobility restrictions between the first wave in June 2020 and the fourth wave in January 2022 of the coronavirus disease-2019 (COVID-19) pandemic in Brazil. PATIENTS AND METHODS: Brazilian citizens answered a self-administered questionnaire that included questions related to personal information, mobility restriction levels, physical activity levels, and the status of mood disorders in June 2020 (n=1853) and January 2022 (n=728). RESULTS: The levels of mobility restrictions (p<0.001), anxiety (p<0.001), and depression (p<0.001) significantly decreased from 2020 to 2022. In June 2020, 23.2% of the participants presented moderate to severe anxiety, and in January 2022, this percentage decreased to 14.8%. In June 2020, 29.6% of the participants presented moderate to severe depressive symptoms, and in January 2022 this percentage decreased to 19.3%. On the contrary, physical activity levels significantly increased between 2020 and 2022 (p<0.001). CONCLUSIONS: During the fourth wave of the COVID-19 pandemic, participants were less restricted and more physically active than in the first wave. Furthermore, anxiety and depression levels were significantly lower in the fourth wave than in the first wave. Despite this reduction, levels of anxiety and depression remain high; therefore, the authors suggest measures to encourage physical activity and promote mental health.

Impact of the COVID-19 pandemic on competitive swimming performance.

OBJECTIVE: This article aims to conduct a comparison of swimming performance during short course national championships (25-m) from 2019 and 2020 (before and during the pandemic). MATERIALS AND METHODS: The data points from the championships will be compared for 5 European countries: Poland, Spain, Russia, Turkey, and Denmark. Times achieved in the finals were calculated by the analysis of variance. Post hoc pairwise comparison analysis was performed using Tukey's test. The analysis plan included the assessment of the main effects and the effect of interactions in the groups of women and men. The strength of the effect was expressed by the partial eta-squared ratio. RESULTS: Two main trends were observed in the results. The first was a greater variation in the results in the group of men than in women (12-5 differences). The second was the development and improvement of sports performance in symmetrical strokes (69% improvement in recorded times measured during the pandemic, e.g., in Poland, women on 50-m breaststroke and butterfly Δ = 0.52, p <0.001 and Δ = 0.32, p = 0.034, men on 50-m and 100-m butterfly Δ = 0.34, p = 0.003 and Δ = 1.21, p <0.001). CONCLUSIONS: The main conclusion of our analysis is that the pandemic influenced the development of sports performance in symmetrical techniques, i.e., in breaststroke and butterfly.

A study on echocardiographic findings in hospitalized patients with connective tissue diseases.

OBJECTIVE: To determine the prevalence of echocardiographic findings and their change over time in patients with connective tissue diseases (CTDs) and to analyse which findings were associated with escalation of immunosuppressive therapy. METHOD: We conducted a retrospective cohort study of consecutive hospitalized patients from a tertiary rheumatology referral centre who received transthoracic echocardiography between 1 January 2006 and 31 December 2015. We tested for associations between echocardiographic findings and treatment escalation via Fisher's exact test; p < 0.05 was considered significant. Escalation of therapy was defined by dosage of glucocorticoids and type of disease-modifying anti-rheumatic drug. The clinical relevance of echocardiographic findings concerning change in immunosuppressive therapy was recorded. RESULTS: In total, 1004 patients were included (865 females), with a total of 1660 echocardiographic examinations. The most frequent findings were mitral, tricuspid, and aortic valve regurgitation (found in 36.7%, 25.4%, and 17.7% of all patients), aortic valve sclerosis (20.1%), left ventricular dysfunction (21.5%), and left atrial dilatation (19.2%). Only pericardial effusions were more frequent in cases with treatment escalation (10.9% of cases with escalated therapy vs 6.9% of cases without, p = 0.007). In 314 patients who received follow-up examinations, echocardiographic findings were found to change between examinations. Only 73 of all 1660 examinations were discussed in depth considering the treatment strategy in the hospital discharge letter. CONCLUSION: Patients with CTDs exhibited a wide, dynamically changing spectrum of echocardiographic abnormalities. Most findings neither reflected disease activity nor appeared to influence the therapeutic regimen.

The efficacy and the adverse reactions of laser-assisted tattoo removal - a prospective split study using nanosecond and picosecond lasers.

BACKGROUND: Laser pulses with nanosecond duration (NSL) have been the golden standard to destroy the pigment particles in skin. It is still controversially discussed whether picosecond pulses (PSL) are superior for tattoo removal. OBJECTIVES: To compare the efficacy and the adverse reactions of nanosecond and picosecond laser pulses in a comparative study. METHODS: The prospective study included 23 subjects with 30 black or coloured tattoos, which were split into two halves treated with either a new PSL (532, 1064 nm) or standard NSL (694 nm). The lasers were applied at regular time intervals of 4 weeks for up to eight treatments. Tattoo clearance (primary endpoint), pain and adverse reactions (secondary endpoints) were appraised by physicians, blinded observers, and by subjects. The extent and duration of adverse reactions were additionally assessed by using a questionnaire and photo-documentation after each treatment session. RESULTS: The tattoo clearance appeared to be more effective for PSL compared to NSL but without statistical significance (P > 0.05). Pretreated tattoos responded better to laser treatments than previously untreated tattoos. Subjects felt significantly less pain with PSL than with NSL (P < 0.001). Transient adverse reactions were statistically less pronounced lasting shorter for PSL as for NSL, especially blistering, pruritus, and burning sensation. Hypopigmentation appeared after NSL treatments only, whereas hyperpigmentation was caused by both lasers. No scarring was detected with either laser. CONCLUSIONS: Both laser systems enable acceptable clearance of most tattoos in the present study. PSL cause less collateral skin damage as compared to NSL.

Does vancomycin resistance increase mortality in Enterococcus faecium bacteraemia after orthotopic liver transplantation? A retrospective study.

BACKGROUND: The relevance of vancomycin resistance in enterococcal blood stream infections (BSI) is still controversial. Aim of this study was to outline the effect of vancomycin resistance of Enterococcus faecium on the outcome of patients with BSI after orthotopic liver transplantation (OLT). METHODS: The outcome of OLT recipients developing BSI with vancomycin-resistant (VRE) versus vancomycin-susceptible Enterococcus faecium (VSE) was compared based on data extraction from medical records. Multivariate regression analyses identified risk factors for mortality and unfavourable outcomes (defined as death or prolonged intensive care stay) after 30 and 90 days. RESULTS: Mortality was similar between VRE- (n = 39) and VSE- (n = 138) group after 30 (p = 0.44) or 90 days (p = 0.39). Comparable results occurred regarding unfavourable outcomes. Mean SOFANon-GCS score during the 7-day-period before BSI onset was the independent predictor for mortality at both timepoints (HR 1.32; CI 1.14-1.53; and HR 1.18; CI 1.08-1.28). Timely appropriate antibiotic therapy, recent ICU stay and vancomycin resistance did not affect outcome after adjusting for confounders. CONCLUSION: Vancomycin resistance did not influence outcome among patients with Enterococcus faecium bacteraemia after OLT. Only underlying severity of disease predicted poor outcome among this homogenous patient population. TRIAL REGISTRATION: This study was registered at the German clinical trials register (DRKS-ID: DRKS00013285).

Effect of mycophenolic acid on inosine monophosphate dehydrogenase (IMPDH) activity in liver transplant patients.

BACKGROUND: Due to the development of immunosuppressants, the focus in transplanted patients has shifted from short-term to long-term survival as well as a better adjustment of these drugs in order to prevent over- and under-immunosuppression. Mycophenolic acid (MPA) is a noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH) and approved for prophylaxis of acute rejection after kidney, heart, and liver transplantation, where it has become a part of the standard therapy. Targeting inosine monophosphate IMPDH activity as a surrogate pharmacodynamic marker of MPA-induced immunosuppression may allow a more accurate assessment of efficacy and aid in limiting toxicity in liver transplanted patients. AIM: Assess IMPDH-inhibition in liver transplant recipients and its impact on biliary/infectious complications, acute cellular rejection (ACR) and liver dependent survival. METHODS: This observational cohort study comprises 117 liver transplanted patients that were treated with mycophenolate mofetil (MMF) for at least 3 months. Blood samples (BS) were collected and MPA serum level and IMPDH activity were measured before (t(0)), 30minutes (t(30)) and 2h after (t(120)) MMF morning dose administration. Regarding MPA, we assessed the area under the curve (AUC). Patients were prospectively followed up for one year and assessed for infectious and biliary complications, episodes of ACR and liver dependent survival. RESULTS: The MPA levels showed a broad interindividual variability at t(0) (2.0±1.8ng/ml), t(30) (12.7±9.0ng/ml) and t(120) (7.5±4.3ng/ml). Corresponding IMPDH activity was at t(o) (23.2±9.5 nmol/h/mg), at t(30) (16.3±8.8 nmol/h/mg) and t(120) (18.2±8.7 nmol/h/mg). With regard to MPA level we found no correlation with infectious or biliary complications within the follow-up period. Patients with baseline IMPDH(a) below the median had significant more viral infections (6 (10.2%) vs. 17 (29.3%); P=0.009) with especially more cytomegalovirus (CMV) infections (1 (3.4%) vs. 6 (21.4%); P=0.03)). Furthermore, patients with baseline IMPDH(a) above the median developed more often non-anastomotic biliary strictures (8 (13.6%) vs. 1 (1.7%), P=0.03). We found the group reaching the combined clinical endpoint of death and re-transplantation showing significantly lower MPA baseline values (t(0) 0.9±0.7 vs. 2.1±1.8µg/ml Mann-Whitney-U: P=0.02). We calculated a simplified MPA(AUC) with the MPA level at baseline, 30 and 120minutes after MPA administration. Whereas we found no differences with regard to baseline characteristics at entry into the study patients with MPA (AUC) below the median experienced significantly more often the combined clinical endpoint (12.1% (7/58) vs. 0.0% (0/57); P=0.002) and had a reduced actuarial re-transplantation-free survival (1.0 year vs. 0.58 years; Log-rank: P=0.007) during the prospective one-year follow-up period. In univariate and multivariate analysis including gender, age, BMI, ACR, MPA (AUC) and IMPDH(a) only BMI, MPA (AUC) and IMPDH(a) were independently associated with reduced actuarial re-transplantation-free survival. CONCLUSION: MPA-levels and IMPDH-activity in liver transplanted patients allows individual risk assessment. Patients with higher IMPDH inhibition acquire more often viral infections. Insufficient IMPDH inhibition is associated with development of non-anastomotic bile duct strictures and reduced re-transplantation-free survival.

Outcome after liver resection for primary and recurrent intrahepatic cholangiocarcinoma.

Background: Liver resection is the only curative therapeutic option for intrahepatic cholangiocarcinoma (ICC), but the approach to recurrent ICC is controversial. This study analysed the outcome of liver resection in patients with recurrent ICC. Methods: Demographic, radiological, clinical, operative, surgical pathological and follow-up data for all patients with a final surgical pathological diagnosis of ICC treated in a tertiary referral centre between 2001 and 2015 were collected retrospectively and analysed. Results: A total of 190 patients had liver resection for primary ICC. The 1-, 3- and 5-year overall survival (OS) rates were 74·8, 56·6 and 37·9 per cent respectively. Independent determinants of OS were age 65 years or above (hazard ratio (HR) 2·18, 95 per cent c.i. 1·18 to 4·0; P = 0·012), median tumour diameter 5 cm or greater (HR 2·87, 1·37 to 6·00; P = 0·005), preoperative biliary drainage (HR 2·65, 1·13 to 6·20; P = 0·025) and local R1-2 status (HR 1·90, 1·02 to 3·53; P = 0·043). Recurrence was documented in 87 patients (45·8 per cent). The mean(s.d.) survival time after recurrence was 16(17) months. Independent determinants of recurrence were median tumour diameter 5 cm or more (HR 1·71, 1·09 to 2·68; P = 0·020), high-grade (G3-4) tumour (HR 1·63, 1·04 to 2·55; P = 0·034) and local R1 status (HR 1·70, 1·09 to 2·65; P = 0·020). Repeat resection with curative intent was performed in 25 patients for recurrent ICC, achieving a mean survival of 25 (95 per cent c.i. 16 to 34) months after the diagnosis of recurrence. Patients deemed to have unresectable disease after recurrence received chemotherapy or chemoradiotherapy alone, and had significantly poorer survival. Conclusion: Patients with recurrent ICC may benefit from repeat surgical resection.

Antecedentes: La resección hepática es la única opción terapéutica curativa para el colangiocarcinoma intrahepático (intrahepatic colangiocarcinoma, iCCA), pero el enfoque terapéutico de la recidiva del iCCA es controvertido. En este estudio se analizaron los resultados de la resección hepática en pacientes con recidiva de un iCCA. Métodos: Se recopilaron de forma retrospectiva y se analizaron los datos demográficos, radiológicos, clínicos, quirúrgicos, de anatomía patológica y de seguimiento de todos los pacientes con diagnóstico anatomopatológico definitivo de iCCA en un centro de referencia terciario entre 2001 y 2015. Resultados: En total, 190 pacientes se sometieron a resección hepática por iCCA primario. La supervivencia global (overall survival, OS) a 1, 3 y 5 años fue del 75%, 57% y 38%, respectivamente. La edad de ≥ 65 años (cociente de riesgos instantáneos, hazard ratio, HR 2,2, i.c. del 95% 1,2­4,0, P = 0,012), la mediana del diámetro del tumor ≥ 5 cm (HR 2,9, i.c. del 95% 1,4­6,0, P = 0,005), el drenaje biliar preoperatorio (HR 2,6, i.c. del 95% 1,3­6,2, P = 0.025) y el estado local R1/2 (HR 1,9, i.c. del 95% 1,0­3,5, P = 0,043) fueron factores pronósticos independientes de la OS. La recidiva se documentó en 87 (45,8%) pacientes. El tiempo medio de supervivencia después de la recidiva fue de 16 ± 2 meses. Los factores pronósticos independientes de recidiva fueron la mediana del diámetro del tumor ≥ 5 cm (HR 1,7, i.c. del 95% 1,1­2,7, P = 0,020), el tumor de alto grado (G3­G4) (HR 1,6, i.c. del 95% 1,0­2,5, P = 0,034) y el estado local R1 (HR 1,7, i.c. del 95% 1,1­2,6, P = 0,020). La resección repetida con intención curativa se realizó en 25 pacientes con iCCA recidivado, con una supervivencia media de 25 meses (i.c. del 95% 16­34 meses) tras el diagnóstico de recidiva. Los pacientes que se consideraron no resecables después de la recidiva se sometieron a quimioterapia o quimiorradioterapia y presentaron una supervivencia significativamente peor. Conclusión: Los pacientes con recidiva de un iCCA pueden beneficiarse de la resección quirúrgica repetida.