[A researcher and physician who gained international fame: Otfrid Foerster (1873-1941) as Nobel Prize candidate]. / "Ein zu internationaler Berühmtheit gelangter Forscher und Arzt": Otfrid Foerster (1873­1941) als Nobelpreiskandidat.

This paper discusses the 17 Nobel Prize nominations for the neurologist and neurosurgeon Otfrid Foerster (1873-1941). Drawing on files from the Stockholm Nobel Prize Archive, primary and secondary literature, it addresses the following questions: what were the reasons given by nominators for Foerster's nominations? What was the relationship between him and his nominators? Why was he ultimately not awarded the Nobel Prize? Most nominators of Foerster's highlighted as the main motive his Handbuch der Neurologie, which he had edited with Oswald Bumke. According to the nominators, this book together with Foerster's neurosurgical work had an enormous impact on contemporary neurology. Furthermore, his "honorable character" was underlined in the nomination letters; however, these reasons were not sufficient for the Nobel Committee: the members classified the handbook as not being original research. Despite this, Foerster's fame is reflected in the present, for example in the Otfrid Foerster Medal, which has been awarded to researchers by the German Society of Neurosurgery since 1953.

Association between meniscal volume and development of knee osteoarthritis.

OBJECTIVE: To assess the association between meniscal volume, its change over time and the development of knee OA after 30 months in overweight/obese women. METHODS: Data from the PRevention of knee Osteoarthritis in Overweight Females study were used. This cohort included 407 women with a BMI ≥ 27 kg/m2, free of OA-related symptoms. The primary outcome measure was incident OA after 30 months, defined by one out of the following criteria: medial or lateral joint space narrowing (JSN) ≥ 1.0 mm, incident radiographic OA [Kellgren and Lawrence (K&L) ≥ 2], or incident clinical OA. The secondary outcomes were either of these items separately. Menisci at both baseline and follow-up were automatically segmented to obtain meniscal volume and delta-volumes. Generalized estimating equations were used to evaluate associations between the volume measures and the outcomes. RESULTS: Medial and lateral baseline and delta-volumes were not significantly associated to the primary outcome. Lateral meniscal baseline volume was significantly associated to lateral JSN [odds ratio (OR) = 0.87; 95% CI: 0.75, 0.99], while other measures were not. Medial and lateral baseline volume were positively associated to K&L incidence (OR = 1.32 and 1.22; 95% CI: 1.15, 1.50 and 1.03, 1.45, respectively), while medial and lateral delta-volume were negatively associated to K&L incidence (OR = 0.998 and 0.997; 95% CI: 0.997, 1.000 and 0.996, 0.999, respectively). None of the meniscal measures were significantly associated to incident clinical OA. CONCLUSION: Larger baseline meniscal volume and the decrease of meniscal volume over time were associated to the development of structural OA after 30 months in overweight and obese women.

Metformin Lowers Body Weight But Fails to Increase Insulin Sensitivity in Chronic Heart Failure Patients without Diabetes: a Randomized, Double-Blind, Placebo-Controlled Study.

PURPOSE: The glucose-lowering drug metformin has recently been shown to reduce myocardial oxygen consumption and increase myocardial efficiency in chronic heart failure (HF) patients without diabetes. However, it remains to be established whether these beneficial myocardial effects are associated with metformin-induced alterations in whole-body insulin sensitivity and substrate metabolism. METHODS: Eighteen HF patients with reduced ejection fraction and without diabetes (median age, 65 (interquartile range 55-68); ejection fraction 39 ± 6%; HbA1c 5.5 to 6.4%) were randomized to receive metformin (n = 10) or placebo (n = 8) for 3 months. We studied the effects of metformin on whole-body insulin sensitivity using a two-step hyperinsulinemic euglycemic clamp incorporating isotope-labeled tracers of glucose, palmitate, and urea. Substrate metabolism and skeletal muscle mitochondrial respiratory capacity were determined by indirect calorimetry and high-resolution respirometry, and body composition was assessed by bioelectrical impedance analysis. The primary outcome measure was change in insulin sensitivity. RESULTS: Compared with placebo, metformin treatment lowered mean glycated hemoglobin levels (absolute mean difference, - 0.2%; 95% CI - 0.3 to 0.0; p = 0.03), reduced body weight (- 2.8 kg; 95% CI - 5.0 to - 0.6; p = 0.02), and increased fasting glucagon levels (3.2 pmol L-1; 95% CI 0.4 to 6.0; p = 0.03). No changes were observed in whole-body insulin sensitivity, endogenous glucose production, and peripheral glucose disposal or oxidation with metformin. Equally, resting energy expenditure, lipid and urea turnover, and skeletal muscle mitochondrial respiratory capacity remained unaltered. CONCLUSION: Increased myocardial efficiency during metformin treatment is not mediated through improvements in insulin action in HF patients without diabetes. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov . Unique identifier: NCT02810132. Date of registration: June 22, 2016.

Cardiovascular Effects of Treatment With the Ketone Body 3-Hydroxybutyrate in Chronic Heart Failure Patients.

BACKGROUND: Myocardial utilization of 3-hydroxybutyrate (3-OHB) is increased in patients with heart failure and reduced ejection fraction (HFrEF). However, the cardiovascular effects of increased circulating plasma-3-OHB levels in these patients are unknown. Consequently, the authors' aim was to modulate circulating 3-OHB levels in HFrEF patients and evaluate: (1) changes in cardiac output (CO); (2) a potential dose-response relationship between 3-OHB levels and CO; (3) the impact on myocardial external energy efficiency (MEE) and oxygen consumption (MVO2); and (4) whether the cardiovascular response differed between HFrEF patients and age-matched volunteers. METHODS: Study 1: 16 chronic HFrEF patients (left ventricular ejection fraction: 37±3%) were randomized in a crossover design to 3-hour of 3-OHB or placebo infusion. Patients were monitored invasively with a Swan-Ganz catheter and with echocardiography. Study 2: In a dose-response study, 8 HFrEF patients were examined at increasing 3-OHB infusion rates. Study 3 to 4: 10 HFrEF patients and 10 age-matched volunteers were randomized in a crossover design to 3-hour 3-OHB or placebo infusion. MEE and MVO2 were evaluated using 11C-acetate positron emission tomography. RESULTS: 3-OHB infusion increased circulating levels of plasma 3-OHB from 0.4±0.3 to 3.3±0.4 mM ( P<0.001). CO rose by 2.0±0.2 L/min ( P<0.001) because of an increase in stroke volume of 20±2 mL ( P<0.001) and heart rate of 7±2 beats per minute (bpm) ( P<0.001). Left ventricular ejection fraction increased 8±1% ( P<0.001) numerically. There was a dose-response relationship with a significant CO increase of 0.3 L/min already at plasma-3-OHB levels of 0.7 mM ( P<0.001). 3-OHB increased MVO2 without altering MEE. The response to 3-OHB infusion in terms of MEE and CO did not differ between HFrEF patents and age-matched volunteers. CONCLUSIONS: 3-OHB has beneficial hemodynamic effects in HFrEF patients without impairing MEE. These beneficial effects are detectable in the physiological concentration range of circulating 3-OHB levels. The hemodynamic effects of 3-OHB were observed in both HFrEF patients and age-matched volunteers. 3-OHB may potentially constitute a novel treatment principle in HFrEF patients.

Heart rate increases in liraglutide treated chronic heart failure patients: association with clinical parameters and adverse events.

Background. Liraglutide, a glucagon-like peptide-1 agonist, is used for treatment of type 2 diabetes and has beneficial cardiovascular properties. However, treatment increases heart rate (HR) and possibly the risk of cardiovascular events in chronic heart failure (CHF) patients. We investigated potential associations between HR changes and clinical, laboratory and echocardiographic parameters and clinical events in liraglutide treated CHF patients. Methods. This was a sub-study of the LIVE study. CHF patients (N = 241) with a left ventricular ejection fraction ≤45% were randomised to 1.8 mg liraglutide daily or placebo for 24 weeks. Electrocardiograms (N = 117) and readouts from cardiac implanted electronic devices (N = 20) were analysed for HR and arrhythmias. Results. In patients with sinus rhythm (SR), liraglutide increased HR by 8 ± 9 bpm (pulse measurements), 9 ± 9 bpm (ECG measurements) and 9 ± 6 bpm (device readouts) versus placebo (all p<.005). Increases in HR correlated with liraglutide dose (p=.01). HR remained unchanged in patients without SR. Serious cardiac adverse events were not associated with HR changes. Conclusions. During 6 months of treatment, HR increased substantially in CHF patients with SR treated with liraglutide but was not associated with adverse events. The long-term clinical significance of increased HR in liraglutide treated CHF patients needs to be determined.

Babinski, Bektherev, Cerletti, Head, and Hitzig: European Neurologists Nominated for the Nobel Prize 1901-1950.

INTRODUCTION: This article provides for the first time an overview of the most often nominated European neurologists for the Nobel Prize, who never received the award. It sheds light on candidates from France, Germany, Italy, Russia, and the UK during the first half of the 20th century. The aim is to highlight the candidates in the field of neurology, to discuss key arguments in the nomination letters, and to raise questions about research trends and hotspots in European neurology 1901-1950. METHODS: Using the Nobel nomination database which contains >5,000 nominations in the prize category physiology or medicine from 1901 to the early 1950s, we listed European neurologists who were nominated more than once during this time period. We then collected nomination letters and jury reports of the prime candidates in the archive of the Nobel Committee for physiology or medicine in Sweden to explore nomination networks and motives. RESULTS: We pinpointed scholars like Joseph Babinski, Vladimir Bektherev, Sir Henry Head, Eduard Hitzig, and Ugo Cerletti. The nomination motives were diverse, ranging from "lifetime" achievements and textbooks to singular (eponymous) discoveries. Issues of scientific priority disputes were central in most nomination letters. CONCLUSION: Nobel Prize nominations constitute a lens through which credit and recognition around major contributions in neurology during the 20th century can be examined. They are unique sources that enable the reconstruction of both research trends in the field and the reputation of individual neurologists.

"He Gave Us the Cornerstone of Sexual Medicine": A Nobel Plan but No Nobel Prize for Eugen Steinach.

This paper reviews the files in the archive of the Nobel Prize Committee for Physiology or Medicine on the Austrian physiologist and pioneering researcher in the emerging fields of urology and sexual medicine: Eugen Steinach (1861-1944). It reconstructs and analyzes why and by whom Steinach was nominated for the Nobel Prize between 1920 and 1938 and discusses the reasons why he never received the award, although the Nobel Committee judged him as prizeworthy. Steinach's Nobel nominee career is extraordinary - not only because of his strong support by renowned international nominators from different scientific and medical disciplines, but also because of the controversial discussions within the Nobel Committee on his achievements, colored by the debates in the international scientific community. The Nobel Prize story adds a new perspective on how contemporary international scholars evaluated Steinach's research on reproduction, "male-making" females, "female-making" males, homosexuality, and the concept of rejuvenation.

Otorhinolaryngologists nominated for the Nobel Prize 1901-1940.

PURPOSE: Several scholars with links to ENT have received the Nobel Prize in physiology or medicine. This overview takes into account ENT Nobel nominees, who never received the award. METHODS: Drawing a comparison on the nominations collected in the archive of the Nobel Committee for physiology or medicine in Stockholm, the Nobel archive database and secondary literature; the paper analyzes for the first time the nominations of Hans Schmid (Stettin), Hermann Gutzmann (Berlin), Karl Wittmaack (Hamburg), and Chevalier Jackson (Chicago). We also bring up nomination letters written by prominent German nominators such as Hermann Schwartze (one of the founders of this journal) and August Lucae. RESULTS: Hans Schmid was the first surgeon to be brought up in a Nobel Prize nomination for an ENT procedure (1901), but since he had passed away 5 years earlier he was not evaluated by the Nobel Committee. Hermann Gutzmann was a strong candidate in 1917 and reached the shortlist because of his pioneering work on stutter, but no Nobel Prize in physiology or medicine was awarded that year. In the 1930's, both Karl Wittmaack and Chevalier Jackson were repeatedly nominated for ENT research. CONCLUSION: Nobel Prize nominations are to date underused sources that shed new light on some scholars in ENT history.

Scientific language trends among Swedish urologists and surgeons 1900-1955.

PURPOSE: Before English took the lead as the prime scientific language among northern European urologists and surgeons, German was widely regarded as the "lingua franca". This shift has to date not been systematically reconstructed. This article provides insights into the question how political and social factors influence how physicians communicate with each other, what they read, and how the constellations of international scientific communities in medicine change over time. METHODS: Through a language analysis of more than 2000 articles, including their references, in major Swedish medical journals as well as surgical doctoral dissertations defended at Swedish universities, this paper explores scientific language trends during the first half of the twentieth century among Swedish physicians for the first time on a large scale. RESULTS AND CONCLUSIONS: The study shows that Swedish urologists and surgeons generally did not switch to English during the years immediately after the First World War, as has been documented in other countries. After a decrease during the first 10 years after the First World War, the German language dominated among Swedish urologists and surgeons from the 1930s until the early 1940s, when English first dominated at large. The rapidity of this process shows that almost all surgical researchers had changed from German to English within just a few years.

Automatic calculation of myocardial external efficiency using a single 11C-acetate PET scan.

BACKGROUND: Myocardial external efficiency (MEE) is defined as the ratio of kinetic energy associated with cardiac work [forward cardiac output (FCO)*mean systemic pressure] and the chemical energy from oxygen consumed (MVO2) by the left ventricular mass (LVM). We developed a fully automated method for estimating MEE based on a single 11C-acetate PET scan without ECG-gating. METHODS AND RESULTS: Ten healthy controls, 34 patients with aortic valve stenosis (AVS), and 20 patients with mitral valve regurgitation (MVR) were recruited in a dual-center study. MVO2 was calculated using washout of 11C -acetate activity. FCO and LVM were calculated automatically using dynamic PET and parametric image formation. FCO and LVM were also obtained using cardiac magnetic resonance (CMR) in all subjects. The correlation between MEEPET-CMR and MEEPET was high (r = 0.85, P < 0.001) without significant bias. MEEPET was 23.6 ± 4.2% for controls and was lowered in AVS (17.2 ± 4.3%, P < 0.001) and in MVR (18.0 ± 5.2%, P = 0.004). MEEPET was strongly associated with both NYHA class (P < 0.001) and the magnitude of valvular dysfunction (mean aortic gradient: P < 0.001, regurgitant fraction: P = 0.009). CONCLUSION: A single 11C-acetate PET yields accurate and automated MEE results on different scanners. MEE might provide an unbiased measurement of the phenotypic response to valvular disease.

Test-retest repeatability of myocardial oxidative metabolism and efficiency using standalone dynamic 11C-acetate PET and multimodality approaches in healthy controls.

BACKGROUND: Myocardial efficiency measured by 11C-acetate positron emission tomography (PET) has successfully been used in clinical research to quantify mechanoenergetic coupling. The objective of this study was to establish the repeatability of myocardial external efficiency (MEE) and work metabolic index (WMI) by non-invasive concepts. METHODS AND RESULTS: Ten healthy volunteers (63 ± 4 years) were examined twice, one week apart, using 11C-acetate PET, cardiovascular magnetic resonance (CMR), and echocardiography. Myocardial oxygen consumption from PET was combined with stroke work data from CMR, echocardiography, or PET to obtain MEE and WMI for each modality. Repeatability was estimated as the coefficient of variation (CV) between test and retest. MEECMR, MEEEcho, and MEEPET values were 21.9 ± 2.7%, 16.4 ± 3.7%, and 23.8 ± 4.9%, respectively, P < .001. WMICMR, WMIEcho, and WMIPET values were 4.42 ± 0.90, 4.07 ± 0.63, and 4.58 ± 1.13 mmHg × mL/m2 × 106, respectively, P = .45. Repeatability for MEECMR was superior compared with MEEEcho but did not differ significantly compared with MEEPET (6.3% vs 12.9% and 9.4%, P = .04 and .25). CV values for WMICMR, WMIEcho, and WMIPET were 10.0%, 14.8%, and 12.0%, respectively, (P = .53). CONCLUSIONS: Non-invasive measurements of MEE using 11C-acetate PET are highly repeatable. A PET-only approach did not differ significantly from CMR/PET and might facilitate further clinical research due to lower costs and broader applicability.

Excellence in orthopaedic surgery: an overview of Nobel Prize nominees 1901-1960 with focus on Friedrich Pauwels and Gerhard Küntscher.

PURPOSE: This paper provides for the first time an overview of orthopaedic surgeons nominated for the Nobel Prize in physiology or medicine during the first six decades of the twentieth century. The study is part of the project "Enacting Excellency: Nobel Prize nominations for surgeons 1901-1960". METHODS: The nomination letters were gathered in the archive of the Nobel Committee at the Karolinska Institute in Solna, Sweden. RESULTS: Among the nominees, we find renowned scholars like Pierre Delbet, Themistocles Gluck, Gerhard Küntscher, Adolf Lorenz, Friedrich Pauwels, Leslie Rush, and Marius Smith-Petersen. The focus of the paper is on nominations for Pauwels (work on biomechanics) and Küntscher (the Küntscher nail). Both were nominated by German surgeons. CONCLUSIONS: Although no orthopaedic surgeon has yet received a Nobel Prize for an orthopaedic achievement, Nobel archive files can help reconstruct important trends in the field during the twentieth century.

Nobel Prize nominees and the rise of urology in Europe around 1900.

PURPOSE: Recent historical research has reconstructed the roads leading to the Nobel Prize for the trained urologists Werner Forssmann (1904-1979) in 1956 and Charles Huggins (1901-1997) in 1966. However, the story of urology and the Nobel Prize does not start and end with the laureates. Taking James Israel (1848-1926), Félix Guyon (1831-1920), and Peter J Freyer (1852-1921) as examples, this paper shows that pioneers in urology were in fact runners-up for the award much earlier. METHODS: The study is based on an analysis of original files in the Nobel Prize archive in Stockholm, scientific publications of the early twentieth century, and secondary literature. RESULT AND CONCLUSION: We argue that Israel's, Guyon's, and Freyer's candidacies reflect not only scientific trends and controversies in urology at the turn of twentieth century, but that the development of the specialty itself was reflected in nominations of physicians working on problems of the genito-urinary system.

Nobel Prize nominees hundred years ago: Abraham Jacobi (1830-1919) and Otto Heubner (1843-1926).

Pediatrics directly and indirectly played an important role in the history of the Nobel Prize in physiology or medicine. However, the history of the Nobel Prize and pediatrics goes beyond the actual laureates. Based on original files in the archive of the Nobel committee of physiology or medicine at the Karolinska Institute in Sweden, this overview aims to shed new light on why the international pioneers of pediatrics Abraham Jacobi (1830-1919) and Otto Heubner (1843-1926) were nominated but never received the prize in 1918. Moreover, Clemens von Pirquet (1874-1929), one of the founders of this journal in 1910 (previously known as Zeitschrift für Kinderheilkunde), also appears in the Nobel records during the first decades of the twentieth century, nominated by Heubner and others. CONCLUSION: We argue that studies of Nobel nominations give new opportunities to study not only the selection process for Nobel laureates, but also to explore which pioneers were seen as the most outstanding at a particular point in time and why. What is known? • Recent historical research suggests that Nobel Prize nominations can help to reconstruct trends in medicine over time. What is new? • This paper takes a new approach on the history of pediatrics and shows why the internationally famous pediatricians Abraham Jacobi, New York, and Otto Heubner, Berlin, were runners-up for the Nobel Prize hundred years ago.

No Silver Medal for Nobel Prize Contenders: Why Anesthesia Pioneers Were Nominated for but Denied the Award.

Taking the examples of the pioneers Carl Ludwig Schleich, Carl Koller, and Heinrich Braun, this article provides a first exploratory account of the history of anesthesiology and the Nobel Prize for physiology or medicine. Besides the files collected at the Nobel Archive in Sweden, which are presented here for the first time, this article is based on medical literature of the early 20th century. Using Nobel Prize nominations and Nobel committee reports as points of departure, the authors discuss why no anesthesia pioneer has received this coveted trophy. These documents offer a new perspective to explore and to better understand aspects of the history of anesthesiology in the first half of the 20th century.