The 12 women who won the Nobel Prize in Medicine or Physiology

Introduction: the Nobel Prize is one of the highest academic honors in the world. Since its first edition, in 1901, until 2021, there have been hundreds of winners. In the Medicine or Physiology category, chosen by the Karolinska Institute in Stockholm, Sweden, 112 awards have been given to 224 laureates, among them, only 12 (5.4%) women.Aims and source of data: with the aim of reviewing the biographies, characteristics, and peculiarities of each woman awarded the Nobel Prize for Medicine or Physiology. Data were analyzed from the following sources: the Award page, websites of the institutions to which some of them have been or are affiliated, books with biographies of Nobel laureates in Medicine or Physiology, and articles in the PubMed database.Summary of findings: the average age when receiving the award was 63.4 years. The most recurrent country of origin was the United States of America, also responsible for the largest number of institutions to which the laureates were affiliated at the time of the award. The academic training of the laureates was quite diverse, ranging among medicine, chemistry, physics, biology, pharmacy, psychology and natural sciences. Five of the 12 laureates did not have children.Comments: the origins and trajectories, although plural, have points in common, such as a fascination with science since childhood and the need to overcome additional barriers throughout their education, because of their sex.Conclusion: investments on a global scale are necessary to increase equity between sexes.

Regulating Research: The Origins and Institutionalization of Research Ethics Committees in Sweden

The year 1966 saw the birth of Sweden’s first formal Research Ethics Committee (rec) at the medical university Karolinska Institute (ki). In the following years other ethical committees were institutionalized, coordinated by a working group steered by the Swedish Medical Research Council (smrc). Research ethical issues of a principled nature were also discussed by the Ethics Delegation of the Swedish Society of Medicine (ssm). Between 1966 and 1975, around 500 research proposals were assessed by rec s in Sweden, and the medical community started to follow certain protocols when preparing applications for ethical review. This paper traces the origins and early development of the rec system in Sweden and offers an analysis of their practices, discussions, and assessments through the reading of meeting protocols and correspondence between central actors. The aim is to sketch out how and why the system of research ethics committees emerged, became institutionalized, and developed in Sweden from the 1960s to the early 1980s. This paper connects to the recent empirical turn in historical research on medical research ethics and regulations, by focusing on how the insiders, i.e., the medical community, reacted to new demands of ethical review. The analysis illustrates how the medical researchers interacted with transnational funders, the Patients Association, a broader public, governmental authorities, and parliamentary politics when developing the Swedish rec system.

Placing women in Cytogenetics: Lore Zech and the chromosome banding technique

Background Scholars agree that Torbjörn Caspersson’s lab at the Institute of Medical Cell Research and Genetics at the Karolinska Institute, Sweden, played a key role in the first description of the so-called Q-banding technique. It laid the foundation for a new era of cytogenetic diagnostics and had a lasting impact in several areas of biology and medicine. Methods Based on a mixed-method approach, essential aspects of the history of human cytogenetics are considered via primary and secondary analysis of biographical interviews as well as the qualitative evaluation of bibliometrics. Drawing on interviews with colleagues of lab member Lore Zech (1923–2013) and contemporary publications, this paper illuminates the role of and contribution by Zech: To what extent is the discovery attached to her and what does her legacy look like today? Results The analysis of the contemporary witness interviews with colleagues, students and junior researchers shows that Lore Zech was a committed member of Caspersson's research group. In addition, memoirs by contemporary colleagues describe her outstanding skills in microscopy. The different sources paint a multifaceted picture. In addition to the historians' patterns of interpretation, different legacies can also be found within the peer group. Conclusions We argue that Zech represent the type of scientist who, although her research was acknowledged with several prizes, so far has not been part of the canon of pioneers of international cytogenetics.

Managing Chronic Pain in Osteoarthritis and Rheumatoid Arthritis

ON DAY 3 of the European Alliance of Associations for Rheumatology (EULAR) 2021 Congress, participants from across the globe accessed the virtual platform to join Jon Lampa, Associate Professor, Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden, and his panel as they explored the challenges and opportunities of managing chronic pain in osteoarthritis and rheumatoid arthritis.

Estimating the tolerance of brachial plexus to hypofractionated stereotactic body radiotherapy: a modelling-based approach from clinical experience

Background Brachial plexopathy is a potentially serious complication from stereotactic body radiation therapy (SBRT) that has not been widely studied. Therefore, we compared datasets from two different institutions and generated a brachial plexus dose–response model, to quantify what dose constraints would be needed to minimize the effect on normal tissue while still enabling potent therapy for the tumor. Methods Two published SBRT datasets were pooled and modeled from patients at Indiana University and the Richard L. Roudebush Veterans Administration Medical Center from 1998 to 2007, as well as the Karolinska Institute from 2008 to 2013. All patients in both studies were treated with SBRT for apically located lung tumors localized superior to the aortic arch. Toxicities were graded according to Common Terminology Criteria for Adverse Events, and a probit dose response model was created with maximum likelihood parameter fitting. Results This analysis includes a total of 89 brachial plexus maximum point dose (Dmax) values from both institutions. Among the 14 patients who developed brachial plexopathy, the most common complications were grade 2, comprising 7 patients. The median follow-up was 30 months (range 6.1–72.2) in the Karolinska dataset, and the Indiana dataset had a median of 13 months (range 1–71). Both studies had a median range of 3 fractions, but in the Indiana dataset, 9 patients were treated in 4 fractions, and the paper did not differentiate between the two, so our analysis is considered to be in 3–4 fractions, one of the main limitations. The probit model showed that the risk of brachial plexopathy with Dmax of 26 Gy in 3–4 fractions is 10%, and 50% with Dmax of 70 Gy in 3–4 fractions. Conclusions This analysis is only a preliminary result because more details are needed as well as additional comprehensive datasets from a much broader cross-section of clinical practices. When more institutions join the QUANTEC and HyTEC methodology of reporting sufficient details to enable data pooling, our field will finally reach an improved understanding of human dose tolerance.

‘The importance of comprehensive and transparent reporting’ In Conversation with Professor Henrik Larsson

In this podcast we speak to Professor Henrik Larsson, Professor of Psychiatric Epidemiology at Orebro University and Karolinska Institute in Sweden, and Editor in Chief of ACAMH's new journal, JCPP Advances.

O85: ENSURE: EUROPEAN INVESTIGATION OF SURVEILLANCE AFTER RESECTION FOR ESOPHAGEAL CANCER

Presenting Author Email: [email protected] Research question Does intensive postoperative surveillance after planned curative resection for oesophageal cancer lead to increased detection of oligometastatic disease, facilitating increased use of tumor-directed therapy, hence improving overall survival? Background and aim Emerging data demonstrate long-term survival after salvage interventions for local or oligometastatic recurrence following planned curative resection for oesophageal cancer, providing rationale for postoperative surveillance. While meta-analyses confirm the survival benefit of chemotherapy (HR0.81, 0.71-0.92), and HER-2 directed therapy (HR0.75, 0.68-0.84) for patients with recurrent or metastatic oesophageal cancer, the effect of surveillance on oncologic outcome and health-related quality-of-life (HRQL) is unknown. There is currently no international consensus regarding the utility of surveillance following curative-intent treatment for oesophageal cancer, with divergent guidelines from ESMO, AUGIS and NCCN. A pilot study including 27 European centres (ENSURE-1) demonstrated wide variation in practice, with tumour markers, CT and PET-CT utilised in 4 (14.8%), 10 (37.0%) and 3 (11.1%), respectively. This multicenter collaborative project aims to determine the independent impact of intensive surveillance on recurrence patterns, oncologic outcome, and HRQL in survivorship, providing the first adequately powered study to address this critical research question. Patients A retrospective observational study of patients undergoing treatment with curative intent for oesophageal cancer at participating Centers from June 2009 to June 2015. Inclusion criteria 1. Age 18 years and above 2. Underwent surgery with curative intent for cTxNxM0 esophageal or esophagogastric junction (Siewert type I, II and III) cancer 3. Salvage surgery after failure of primary endoscopic or oncologic treatment will be included Exclusion criteria 1. Endoscopic therapy or definitive oncological treatment as sole therapy for esophageal cancer 2. Missing follow-up data Comparator Outcomes will be compared among patients managed with intensive surveillance (IS) compared with standard surveillance. IS will be defined as the routine use of CT/PET-CT for surveillance, at least annually, for at least the first three postoperative years. Each participating centre will be classified as undertaking IS or standard surveillance (SS) according to data submitted in the pilot study (ENSURE-1). Outcomes The primary endpoint of this study is: • Overall survival The secondary endpoints of this study are: • Disease-specific survival • Observed disease-free survival • HRQL o Prespecified EORTC QLQ-C30, QLQ-OG25 items • Recurrence patterns and treatment o Site of disease at initial recurrence o Oligometastatic disease at initial recurrence o Anastomotic disease at initial recurrence o Palliative chemotherapy, chemoradiation and radiation use o Treatment for oligometastatic and anastomotic recurrence (surgery, radiation, chemotherapy only) Study design Power calculation and sample size Power calculations are based on Sisic et al. demonstrating a 5% increase in 5-year overall survival with standardized follow-up in a propensity score matched analysis. Based on an initial feasibility survey of 18 Centers, current estimated number of cases per year for enrolled Centers is 885, therefore it is anticipated that the 5-year study period should capture approximately 4425 patients, of whom 31% undergo high intensity surveillance with cross-sectional imaging, with a minimum postoperative follow-up of 3 years. Using a log-rank analysis to detect a 5% difference in overall survival with sigma of 0.05, with 1371 of 4425 patients in the IS group, the study is powered to 90.4%, while accounting for a potential 20% exclusion rate, the study is powered to 83.1% with current enrolled Centers. Data collection and study definitions Where possible, data will be collected from prospectively maintained databases at participating Centers. Collected data will be entered into a standardized data collection spreadsheet “ENSURE Study - Datasheet” (attached). Variables will be coded at source by Co-Investigators according to standardized coding. Briefly, collected data will include: • Demographics • Co-morbidities and performance status • Histologic type • Tumor location • Clinical stage and grade • Pathologic stage, grade, treatment response and margins • Neoadjuvant therapy details • Operative details • Overall postoperative morbidity • Recurrence and associated treatment • Survival data • HRQOL o ENSURE database will be linked to include relevant HRQL data from a previous study (LASER) Registration The study has been registered on ClinicalTrials.gov (NCT03461341). Statistical Approach Data will be analyzed using SPSS® (v.23.0) software (SPSS, Chicago, IL, USA). For the multivariable analyses, all clinically relevant variables will be inputted into multivariable linear, logistic or Cox proportional hazards regression models. Team and infrastructure An international multidisciplinary collaborative team has been assembled via the Young Investigator Group of the European Society for Diseases of the Esophagus for the conduct of this study, with 27 centres signed up to participate in the pilot study to date. The study will be initiated from St. James's Hospital, Dublin, Ireland; the Karolinska Institute, Stockholm, Sweden; and Imperial College London, London, England. Steering committee: Jessie Elliott (Dublin), Fredrik Klevebro (Stockholm), Sheraz Markar (London), Lucas Goense (Utrecht), Melody Ni (London – statistician), Pernilla Lagergran (Stockholm – HRQL researcher) Supervisory committee: John V Reynolds (Dublin), Magnus Nilsson (Stockholm), George Hanna (London), Giovanni Zaninotto (Padova). Infrastructure: A dedicated biostatistician (Dr Melody Ni, Imperial College London) is a collaborator on the current project and will provide expertise with respect to design and data analysis. A researcher with expertise in HRQL assessment (Professor Pernilla Lagergren, Karolinska Institute) is also a named collaborator on the present project.

Developing innovation governance readiness in regenerative medicine: lessons learned from the Macchiarini crisis

The generation and clinical adoption of workable therapies in regenerative medicine has been slow, despite its alleged potential to relieve suffering and improve health outcomes. This has been explained by a fundamental difference between advanced cell and gene therapies and conventional drug- and device-based therapies, raising questions about how the readiness of existing healthcare systems to adopt such therapies can be evaluated and improved. In this paper, we use the lessons learned from the Macchiarini crisis at the Karolinska Institute in Sweden to take the first step in formulating the concept of innovation governance readiness. We propose it as a tool to help evaluate and improve the ability of private, public and civil society actors to work together to build and put into practice therapies based on emerging medical technologies such as regenerative medicine.

Estimating the tolerance of Brachial Plexus to hypofractionated Stereotactic Body Radiotherapy – A modelling-based approach from clinical experience.

Background: Brachial plexopathy (BP) is a potentially serious complication from stereotactic body radiation therapy (SBRT) that has not been widely studied. Therefore, we compared datasets from two different institutions and generated a brachial plexus dose-response model, to quantify what dose constraints would be needed to minimize the effect on normal tissue while still enabling potent therapy for the tumor.Methods: Two published SBRT datasets were pooled and modeled from patients at Indiana University and the Richard L. Roudebush Veterans Administration Medical Center from 1998 to 2007, as well as the Karolinska Institute from 2008 to 2013. All patients in both studies were treated with SBRT for apically located lung tumors localized superior to the aortic arch. Toxicities were graded according to Common Terminology Criteria for Adverse Events (CTCAE) and a probit dose response model was created with maximum likelihood parameter fitting.Results: This analysis includes a total of 89 brachial plexus Dmax values from both institutions. Among the 14 patients who developed BP, the most common complications were grade 2, comprising 7 patients. The median follow-up was 30 months (range 6.1-72.2) in the Karolinska dataset, and Indiana had a median of 13 months (range 1-71). Both studies had a median range of 3 fractions, but in the Indiana dataset 9 patients were treated in 4 fractions and the paper did not differentiate which ones were which, so our analysis is considered to be in 3-4 fractions, which is one of the main limitations. The probit model showed that the risk of BP with Dmax of 26 Gy in 3-4 fractions is 10%, and 50% with Dmax of 70 Gy in 3 -4 fractions.Conclusions: This analysis is only a preliminary result because more details are needed, and more comprehensive datasets are needed from a much broader cross-section of clinical practices. When more institutions join the QUANTEC and HyTEC methodology of reporting sufficient details to enable data pooling, our field will finally reach an improved understanding of human dose tolerance.

DNA methylation differences at birth after conception through ART

STUDY QUESTION Is there a relation between ART and DNA methylation (DNAm) patterns in cord blood, including any differences between IVF and ICSI? SUMMARY ANSWER DNAm at 19 CpGs was associated with conception via ART, with no difference found between IVF and ICSI. WHAT IS KNOWN ALREADY Prior studies on either IVF or ICSI show conflicting outcomes, as both widespread effects on DNAm and highly localized associations have been reported. No study on both IVF and ICSI and genome-wide neonatal DNAm has been performed. STUDY DESIGN, SIZE, DURATION This was a cross-sectional study comprising 87 infants conceived with IVF or ICSI and 70 conceived following medically unassisted conception. The requirement for inclusion in the study was an understanding of the Swedish language and exclusion was the use of donor gametes. PARTICIPANTS/MATERIALS, SETTING, METHODS Participants were from the UppstART study, which was recruited from fertility and reproductive health clinics, and the Born into Life cohort, which is recruited from the larger LifeGene study. We measured DNAm from DNA extracted from cord blood collected at birth using a micro-array (450k array). Group differences in DNAm at individual CpG dinucleotides (CpGs) were determined using robust linear models and post-hoc Tukey’s tests. MAIN RESULTS AND THE ROLE OF CHANCE We found no association of ART conception with global methylation levels, imprinted loci and meta-stable epialleles. In contrast, we identify 19 CpGs at which DNAm was associated with being conceived via ART (effect estimates: 0.5–4.9%, PFDR < 0.05), but no difference was found between IVF and ICSI. The associated CpGs map to genes related to brain function/development or genes connected to the plethora of conditions linked to subfertility, but functional annotation did not point to any likely functional consequences. LIMITATIONS, REASONS FOR CAUTION We measured DNAm in cord blood and not at later ages or in other tissues. Given the number of tests performed, our study power is limited and the findings need to be replicated in an independent study. WIDER IMPLICATIONS OF THE FINDINGS We find that ART is associated with DNAm differences in cord blood when compared to non-ART samples, but these differences are limited in number and effect size and have unknown functional consequences in adult blood. We did not find indications of differences between IVF and ICSI. STUDY FUNDING/COMPETING INTEREST(S) E.W.T. was supported by a VENI grant from the Netherlands Organization for Scientific Research (91617128) and JPI-H2020 Joint Programming Initiative a Healthy Diet for a Healthy Life (JPI HDHL) under proposal number 655 (PREcisE Project) through ZonMw (529051023). Financial support was provided from the European Union’s Seventh Framework Program IDEAL (259679), the Swedish Research Council (K2011-69X-21871-01-6, 2011-3060, 2015-02434 and 2018-02640) and the Strategic Research Program in Epidemiology Young Scholar Awards, Karolinska Institute (to A.N.I.) and through the Swedish Initiative for Research on Microdata in the Social And Medical Sciences (SIMSAM) framework grant no 340-2013-5867, grants provided by the Stockholm County Council (ALF-projects), the Strategic Research Program in Epidemiology at Karolinska Institutet and the Swedish Heart-Lung Foundation and Danderyd University Hospital (Stockholm, Sweden). The funders had no role in study design, data collection, analysis, decision to publish or preparation of the manuscript. The authors declare no competing interests. TRIAL REGISTRATION NUMBER N/A.