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Abstract Background Patients with heart failure with preserved ejection fraction (HFpEF) commonly experience exercise intolerance, resulting in reduced cardiorespiratory fitness. This is characterised by a decreased maximal oxygen uptake (V̇O2peak), which is determined by the product of cardiac output (CO) and arteriovenous oxygen difference (a-vDO2). While exercise training has been shown to improve V̇O2peak in HFpEF patients, the effects on CO remain unclear. The aim of this study is to systematically review and analyse the current evidence on the effects of supervised exercise training on CO in patients with HFpEF. Methods We will systematically search for literature describing the effects of supervised exercise training on CO in patients with HFpEF. All eligible studies published before 30 June 2023 in the following electronic databases will be included: MEDLINE (Ovid), Embase (Ovid), SPORTDiscus (EBSCOhost), and CENTRAL (Cochrane Library). Effect sizes will be extracted for CO before and after a supervised exercise training intervention at rest and maximal exercise. Mass of heterogeneity (I 2) will be calculated, and either fixed-effect models or random-effect models will be used for meta-analysis. To detect a potential publication bias, funnel plot analyses will be performed. Discussion While several studies have reported a positive effect of supervised exercise training on cardiorespiratory fitness, attempts to assess the underlying determinants of V̇O2peak, CO, and a-vDO2 are much scarcer, especially in patients with HFpEF. From a physiological perspective, measuring CO before and after supervised exercise training seems to be a reasonable way to accurately operationalise a potential improvement in cardiac function. Systematic review registration PROSPERO CRD42022361485.

Background: Different lines of evidence imply that metformin could alter steroid hormone homeostasis and thereby improve social impairment. Here, we tried to correlate the impact of metformin treatment on alterations in steroid hormones and autism spectrum traits before versus after treatment with metformin. Material & methods: Urine steroid hormones were measured using gas chromatography mass spectrometry in 12 male subjects (54.2 ± 9.1 years, 177.3 ± 4.1 cm, 80 ± 10.4 kg) and 7 female subjects (64.14 ± 18.0 years, 162.7 ± 4.1 cm, 76.1 ± 10.4 kg). Furthermore, a questionnaire on autism spectrum traits (Autism Spectrum Questionnaire]) was administered prior to and after metformin treatment. Results: Overall, a decrease of steroid hormones were detected, which were most pronounced in the metabolites of corticosterone, deoxycortisol, cortisol, as well as androgens. These remained after Bonferroni correction (three classes: glucocorticoid, mineralocorticoid, androgens). No effect on autism spectrum traits (social skills, attention switching skills, attention to detail skills, communication skills, imagination skills), was identified pre versus post metformin treatment. Discussion: The decreased steroid hormone levels are based on different mechanisms; one effect is likely via mitochondria, another effect via activated protein kinase prior to post treatment. The finding on autistic traits must be taxed as negative and do not directly provide an argument for using metformin in the treatment of autism.

Abstract Fortunately, fatal accidents while high-altitude mountaineering have decreased in recent years, but the number of emergencies has increased. These nonfatal emergencies might represent situations where alpinists are stranded (emergencies in which alpinists are no longer able to continue their tour on their own because of, for example, exhaustion, equipment problems, or weather). We analyzed 4596 cases of high-altitude-mountaineering emergencies in the period 2009 to 2020 from the SAC (Swiss Alpine Club) emergency registry. In total, 1951 cases (41.6%) were due to being stranded, 1348 cases were due to falls (28.7%), and 352 cases were due to illness (7.5%); these were the three most common classes. In cases of being stranded, 90% of alpinists were uninjured or not seriously injured. In addition, we found only eight fatal cases. More than 50% of cases occurred while ascending a summit above 4000 m. The main causes of becoming stranded were exhaustion and weather changes. These findings suggest that alpinists contact rescue organizations before experiencing serious troubles; these situations thus present risks and dangers both to those stranded and to emergency services. Since exhaustion and weather changes are the two main causes, adequate preparation and tour planning may help prevent such emergencies.

BackgroundThe efficiency of aerobic energy provision to working skeletal muscle is affected by aerobic fitness and a prominent insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE-I/D) gene for the major modulator of tissue perfusion. We assessed whether variability in the fitness state is dependent on the contribution of multiple aspects of oxygen transport to the development of muscle power, and the respective control coefficients, are associated with the ACE-I/D genotype.MethodsTwenty-five women and 19 men completed a ramp test of cycling exercise to exhaustion during which serial steps of oxygen transport [oxygen uptake (L O2 min−1) (VO2), minute ventilation in (L min−1) (VE), cardiac output in equivalents of L min−1 (Q), arterial oxygen saturation (SpO2), muscle oxygen saturation (SmO2), and total hemoglobin concentration (g dL−1) (THb) in Musculus vastus lateralis and Musculus gastrocnemius, respiration exchange ratio (RER)], blood lactate and glucose concentration, were continuously monitored. The contribution/reliance of power output (PO) on the parameters of oxygen transport was estimated based on the slopes in Pearson's moment correlations (|r| > 0.65, p < 0.05) vs. power values over the work phase of the ramp test, and for respective fractional changes per time (defining control coefficients) over the rest, work, and recovery phase of the ramp test. Associations of variability in slopes and control coefficients with the genotype and aerobic fitness were evaluated with ANOVA.ResultsAll parameters characterizing aspects of the pathway of oxygen, except THb, presented strong linear relationships [(|r| > 0.70) to PO]. Metabolic efficiency was 30% higher in the aerobically fit subjects [peak oxygen uptake (mL O2 min−1) (VO2peak) ≥ 50 ml min−1 kg−1], and energy expenditure at rest was associated with the fitness state × ACE-I/D genotype, being highest in the fit non-carriers of the ACE D-allele. For VO2, VE, and RER the power-related slopes of linear relationships during work demonstrated an association with aerobic fitness, being 30–40% steeper in the aerobically fit than unfit subjects. For VE the power-related slope also demonstrated an association with the ACE-I/D genotype. For increasing deficit in muscle oxygen saturation (DSmO2) in Musculus vastus lateralis (DSmO2 Vas), the power-related slope was associated with the interaction between aerobic fitness × ACE-I/D genotype.ConclusionLocal and systemic aspects of aerobic energy provision stand under influence of the fitness state and ACE-I/D genotype. This especially concerns the association with the index of the muscle's mitochondrial respiration (SmO2) which compares to the genetic influences of endurance training.

Background: We recently reported that metformin administration has substantial effects on steroid hormone concentrations. In this study, we specifically explored which enzymatic activities were affected before a first treatment versus after a time of metformin treatment. Material and Methods: Twelve male subjects (54.2 ± 9.1 years, 177.3 ± 4.1 cm, 80 ± 10.4 kg) and seven female subjects (57.2 ± 18.9 years, 162.7 ± 4.1 cm, 76.1 ± 10.4 kg) were recruited based on an indication of metformin. Prior to the first intake of metformin and after 24 h, urine collections were performed. Urine steroid analysis was completed using gas chromatography–mass spectrometry. Results: The average reduction in steroid hormone concentrations after the metformin treatment was substantial and relatively equally distributed in all metabolites and the sum of all metabolites with 35.4%. An exception was dehydroepiandrosterone, with a decrease of almost three hundred percent of average concentration. In addition, the sum of all cortisol metabolites and 18-OH cortisol (indicative of oxidative stress) were lower after the metformin treatment. Furthermore, significant inhibition of 3ß-HSD activity was detectable. Discussion: Effects prior to and after the metformin treatment on inhibiting 3ß-HSD activity were detected in line with findings from others. Furthermore, the pattern of a reduction, for example, in the sum of all glucocorticoids following the metformin treatment supported an effect on oxidative stress, which was further supported by the reduction in 18-OH cortisol. Nevertheless, we do not understand all steps in the complex pattern of the enzymes that affect steroid hormone metabolism and, consequently, further studies are necessary to improve our understanding.

IntroductionThe insertion/deletion (I/D) polymorphism in the gene for the major regulator of vascular tone, angiotensin-converting enzyme-insertion/deletion (ACE-I/D) affects muscle capillarization and mitochondrial biogenesis with endurance training. We tested whether changes of leg muscle oxygen saturation (SmO2) during exhaustive exercise and recovery would depend on the aerobic fitness status and the ACE I/D polymorphism.MethodsIn total, 34 healthy subjects (age: 31.8 ± 10.2 years, 17 male, 17 female) performed an incremental exercise test to exhaustion. SmO2 in musculus vastus lateralis (VAS) and musculus gastrocnemius (GAS) was recorded with near-IR spectroscopy. Effects of the aerobic fitness status (based on a VO2peak cutoff value of 50 ml O2 min−1 kg−1) and the ACE-I/D genotype (detected by PCR) on kinetic parameters of muscle deoxygenation and reoxygenation were assessed with univariate ANOVA.ResultsDeoxygenation with exercise was comparable in VAS and GAS (p = 0.321). In both leg muscles, deoxygenation and reoxygenation were 1.5-fold higher in the fit than the unfit volunteers. Differences in muscle deoxygenation, but not VO2peak, were associated with gender-independent (p > 0.58) interaction effects between aerobic fitness × ACE-I/D genotype; being reflected in a 2-fold accelerated deoxygenation of VAS for aerobically fit than unfit ACE-II genotypes and a 2-fold higher deoxygenation of GAS for fit ACE-II genotypes than fit D-allele carriers.DiscussionAerobically fit subjects demonstrated increased rates of leg muscle deoxygenation and reoxygenation. Together with the higher muscle deoxygenation in aerobically fit ACE-II genotypes, this suggests that an ACE-I/D genotype-based personalization of training protocols might serve to best improve aerobic performance.

BackgroundThis study aimed to analyze falls regarding their demographic characteristics, severity, frequency over time, and the localization of injuries while high-altitude mountaineering in the Swiss Alps.MethodsData on fall-related emergencies during mountaineering between 2009 to 2020 from the Swiss Alpine Club central registry were analyzed retrospectively. The variables age, sex, time of occurrence, severity of an event quantified by NACA-Score (National Advisory Committee for Aeronautics Score), and injury localization were examined descriptively. Changes in injury severity, number of total emergencies, and fatal emergencies over time were analyzed using linear regression models.ResultsOut of 1347 (28.7%) victims of fall-related emergencies, 1027 were men (76.2%) and 320 (23.8%) women. Around 70% of the cases happened during summer in July and August. The mean age was 49.9 ± 14.9 years for men and 51.3 ± 14.4 years for women with no between-sex difference. Higher NACA-Scores were found in men than women (3.6 ± 2.2 vs. 3.1 ± 1.6; p < 0.01). Approximately 80% of all victims originated from the countries close to the Alps (Switzerland, Germany, Italy, France, and Austria). There was a slight decrease of total cases (R2 = 0.104) and fatal cases over time (R2 = 0.183). NACA-Scores decreased over time (R2 = 0.168). Likewise, risk aversion decreased over time as the severity of emergencies decreased. Injuries occurred predominantly at the extremities (90%). Out of all cases, 228 fatal emergencies (16.9%) could be identified of which 82 occurred while climbing one of the classic 4000ers.ConclusionsThe decrease of the number and severity implies that security standards of the average alpinist have in tendency increased. Nevertheless, the high number of emergencies on classic 4000ers implies that despite the potentially improved security standards, many tours on famous mountains still have high requirements in terms of alpine skills.

Background: Metformin is an effective treatment option for type 2 diabetes mellitus, and it is, to this day, the most prescribed oral antiglycaemic drug. Besides its effects mainly on mitochondrial activity, an off-label use came up as a pharmaceutical for subjects with a diagnosis of polycystic ovarian syndrome (PCOS) along with altered steroid hormone homeostasis. Besides these effects, even an influence on mood and social behavior was described, leading to the aim of this case report to elucidate the effects before versus after treatment with metformin on steroid hormones and social behavior. Methods: A female patient with diagnosed PCOS was analyzed three times for steroid hormone levels. The first analysis was performed before treatment; the second, after a period of 71 days with metformin at 2 × 500 mg; and the third, after a total of 144 days with metformin at 2 × 500 mg. Spot urine probes were taken in the morning for a combined gas chromatography–mass spectrometry (GC-MS), and the steroid levels were adjusted for creatinine excretion. A questionnaire on social behavior (Autism Spectrum Questionnaire) was administered before treatment and after 71 days. Results: A decrease in all the steroid hormones measured was detected after 71 and 144 days of treatment with metformin, being more pronounced after 144 days of treatment and highly significant (p < 0.001). Furthermore, in the untreated state, the class of corticosterone metabolites showed increased values compared to the female reference values for TH-11-DH-corticosterone, TH-corticosterone, and 5a-TH-corticosterone. In the class of estrogen metabolites, increased values compared to the reference values were detected for 17b-estradiol; in the class of 11-deoxycortisol metabolites, an increase in TH-11-deoxycortisol was detected. For the class of cortisol metabolites, increased values compared to the reference values were detected for cortisone, TH-cortisone, a-cortolone, b-cortolone, 20b-dihydrocortisone, cortisol, TH-cortisol, 5a-TH-cortisol, a-cortol, 20b-dihydrocortisol, and 6b-OH-cortisol. No increases in androgen metabolites were detected. Interestingly, weight decreased from 93.4 kg to 91.3 kg after 71 days and fell to 82.7 kg after 144 days of treatment. The skeletal muscle mass was 30.1 kg at the first visit, decreasing to 29.9 kg and to 27.5 kg. No significant difference in the social behavior score from baseline to after 71 days of treatment was detected. Discussion: Metformin improved the steroid hormone profiles from levels above the upper reference values to the middle of the reference values after 71 days and to the lower ends of the reference values after 144 days of treatment. This implies not only that metformin has an effect on steroid hormone levels, but in addition that the efficacy of the pharmaceutical seems to depend on the time interval from intake. To summarize, in this patient, steroid hormones were affected but social behavior was not. If no effect of metformin on social behavior exists, this must be supported by further cases.

Background: Evidence exists that steroid hormones are altered in individuals with autism, especially androgens. Despite lower prevalence in girls than boys, evidence of potential alterations in progesterone metabolites is sparse, so the aim of this study was to elucidate different progesterone metabolites in affected children with autism versus healthy controls. Material and Methods: Circadian urine samples from 48 boys and 16 girls with autism spectrum disorders and a matched case–control group were analysed for progesterone metabolites by gas chromatography–mass spectrometry and normalised for creatinine excretion. Results: In boys with autism, the majority of progesterone metabolites were reduced, such as progesterone, 6a-OH-3a5b-TH-progesterone, or 20a-DH-progesterone (p < 0.01 for all). In girls with autism, a similar pattern of reduction in progesterone metabolites was detected; however, potentially due to the relatively small sample, this pattern was only detectable on the level of a trend. Discussion: As stated, androgen levels are higher in boys and girls with autism, but evidence for progesterone metabolites is much sparser. The pattern of a decrease in progesterone metabolites suggests the existence of an altered routing of steroid metabolites, probably in combination with a dysregulation of the HPAG axis. As, recently, increased CYP17A1 activity has been suggested, the stronger routing towards androgens is further implied in line with our findings of lower progesterone concentrations in boys and girls with autism than healthy controls.

Background: Social behavior is mediated by steroid hormones, whereby various lines of evidence indicate that metformin might improve the symptoms of social withdrawal. This directly yields to the aim of the study to correlate the impact of metformin treatment on the potential alterations in steroid hormone homeostasis, which is ultimately impacting social behavior. Therefore, urinary samples of patients before and after treatment with metformin will be correlated to social behavior to elucidate potential changes in steroid hormone profiles and social behavior. Material and Methods: An observational study in healthy adults with a new indication for metformin. Steroid hormone analysis, including the most prominent androgen, estrogen, progesterone, aldosterone, corticosterone, cortisone and cortisol metabolites analyzed with gas chromatography–mass spectrometry and a questionnaire on social behavior (Autism Spectrum Questionnaire (AQ)) will be administered prior to and after around a 12-week phase of metformin treatment. Discussion: It is likely that due to different pathophysiological mechanisms such as an effect on the respiratory chain in mitochondria or via AMP-activated protein kinase, a general alteration of steroid hormone levels can be detected prior to post treatment. The encompassing measurement of steroid hormones shall give hints concerning the involvement of specific cascades yielding potential pharmacological targets for future research.

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Background: Epitestosterone [E] has for a long time been considered as a biologically inactive androgen. However, recently a distinct antiandrogenic activity of this naturally occurring endogenous epimer of Testosterone has been demonstrated. Especially the ratios of testosterone/epitestosterone (T/E) seem to be key as inhibition of epitestosterone on androgen activity was postulated. As in autism, a higher androgen activity was implied. We, therefore, suggested higher levels of T/E ratios of children with autism versus children with typical development. Methods: Urine probes of 22 girls with autism (BMI 18.7 ± 4.3; average age 12.3 ± 3.8 years) and a sample of 51 controls (BMI 17.0 ± 2.6; average age 11.9 ± 4 years), as well as 61 boys with autism (BMI 17.04 ± 2. average age 11.9 ± 2.5 years) and 61 control boys (BMI 17.0 ± 2.6; average age 11.1 ± 3.0 years), were analyzed with gas chromatography mass spectrometry. RESULTS: The average T/E ratio of all boys with autism was 2.5 ± 1.8 versus 2.4 ± 1.3 in boys with typical development, respectively. No significant difference between boys with autism versus boys with typical development could be detected (p = 0.977). In girls with autism, the average T/E ratio was 1.4 ± 0.9 versus 2.0 ± 1.4 in girls with typical development, whereby a significant difference could be detected (p = 0.0285). Further, polynomial analysis of the third degree were conducted, showing a dependence from age with reasonable coefficients of determination (0.075 < R2 < 0.22, all samples). Discussion: As encompassing steroid hormone analysis are expensive and work-intensive, we hoped to find an easily applicable biomarker to support diagnostics in autism. However, as a relatively small sample of only 22 girls with autism were analyzed and menstrual cycle and pubertal status were only partly controllable through the matching of BMI and age, the question arises if it was an incidental finding. Nevertheless, one suggestion might be that epitestosterone has the effect of a competitive inhibition on the androgen receptor, which would probably help to explain the higher prevalence of autism in boys as compared to girls. Presumably, as no significant difference was detected in boys, this effect might not be as relevant from a steroid hormone perspective, and other effects such as altered 17/20-hydroxylase activity as previously shown in boys and girls with autism seem to have more relevance. Analysis of larger samples, including plenty of metabolites and enzymatic cascades, as well as the role of backdoor pathway activity of androgen synthesis of girls with autism, are demanded in order to validate current findings of altered steroid hormones in autism.

Background: Conventional forms of endurance training based on shortening contractions improve aerobic capacity but elicit a detriment of muscle strength. We hypothesized that eccentric interval training, loading muscle during the lengthening phase of contraction, overcome this interference and potentially adverse cardiovascular reactions, enhancing both muscle metabolism and strength, in association with the stress experienced during exercise. Methods: Twelve healthy participants completed an eight-week program of work-matched progressive interval-type pedaling exercise on a soft robot under predominately concentric or eccentric load. Results: Eccentric interval training specifically enhanced the peak power of positive anaerobic contractions (+28%), mitigated the strain on muscle’s aerobic metabolism, and lowered hemodynamic stress during interval exercise, concomitant with a lowered contribution of positive work to the target output. Concentric training alone lowered blood glucose concentration during interval exercise and mitigated heart rate and blood lactate concentration during ramp exercise. Training-induced adjustments for lactate and positive peak power were independently correlated (p < 0.05, |r| > 0.7) with indices of metabolic and mechanical muscle stress during exercise. Discussion: Task-specific improvements in strength and muscle’s metabolic capacity were induced with eccentric interval exercise lowering cardiovascular risk factors, except for blood glucose concentration, possibly through altered neuromuscular coordination.

The aim of this multiple-case study was to find out how the most successful team of the 1971 Mathematical Olympiad in Hungary developed professionally. It is impressive that in 1971, no fewer than four participants on the Hungarian team received gold medals and four participants received silver medals. Seven of the eight analyzed participants on the team came from a grammar school in Budapest. Three of the four gold medal winners achieved remarkable academic positions. On average, professional positions were achieved (as scored by the magnitude prestige scale) well above the average for a normal grammar school sample. Interestingly, the calculated average of the Hungarian team (156.5 ± 15.5) was slightly higher than that of the comparison team from Sweden (142.8 ± 30.5), but this difference was not significant (p = 0.351). In principle, excellence seems to result in excellence. For several former participants on the Hungarian team, it was shown that they continued to be extremely successful in the field of mathematics, with a thematic focus in the field of statistics and probability calculations.