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Rayan Nikkilä,1– 4 Elli Hirvonen,1 Janne Pitkäniemi,1,5,6 Jari V Räsänen,7 Nea K Malila,1 Antti Mäkitie2,3,8 1Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland; 2Department of Otorhinolaryngology, Head and Neck Surgery, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 3Research Program in Systems Oncology, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 4Päijät-Häme Joint Authority for Health and Wellbeing, Department of Oral and Maxillofacial Surgery, Lahti Central Hospital, Lahti, 15850, Finland; 5Unit of Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland; 6Department of Public Health, University of Helsinki, Helsinki, Finland; 7Department of General Thoracic and Oesophageal Surgery, Heart and Lung Centre, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; 8Division of Ear, Nose and Throat Diseases, Department of Clinical Sciences, Intervention and Technology, Karolinska Institutet and Karolinska Hospital, Stockholm, SwedenCorrespondence: Antti Mäkitie, Helsinki University Hospital, Department of Otorhinolaryngology, Head and Neck Surgery, P.O.Box 263, FI-00029 HUS, Helsinki, Finland, Tel +358-50-428 6847, Email antti.makitie@helsinki.fiPurpose: The occurrence of a second primary cancer (SPC) after primary esophageal carcinoma (EC) or gastric cardia carcinoma(GCC) is well acknowledged. However, previous research on the risk of SPC among these patients has been predominantly conducted in Asian countries. Yet, notable population-dependent variation in histological types and risk profiles exists. This register-based study assesses the histology-specific risk of SPC among individuals initially diagnosed with a first primary EC or GCC.Patients and Methods: We obtained data on 7197 patients diagnosed with EC/GCC in Finland between 1980 and 2022 from the Finnish Cancer Registry. Standardized incidence ratios (SIR) of SPC were subsequently calculated relatively to the cancer risk of the general population.Results: The average and median follow-up times were 2.8 years and 10.5 months. Adenocarcinomas and squamous cell carcinomas comprised 57.8% (n = 4165) and 36.6% (n = 2631) of all cases, respectively. An increased SIR was noted among EC/GCC patients after 15– 20 years of follow-up (SIR 1.49, 95% CI: 1.01– 2.11). Among adenocarcinoma patients, an increased SIR for SPCs of the digestive organs was seen in the 40– 54-year-old group (SIR 9.86, 95% CI: 3.62– 21.45). Squamous cell carcinoma patients displayed increased SIRs for cancer of the mouth/pharynx (SIR 3.20, 95% CI: 1.17– 6.95) and respiratory organs (1.77, 1.07– 2.76).Conclusion: Healthcare professionals should be aware of the increased risk of SPCs occurring in the mouth/pharynx, respiratory and digestive organs in survivors of EC/GCC. Patients should be advised about this risk and remain alert for symptoms, even beyond the standard 5-year follow-up period.Keywords: esophageal squamous cell carcinoma, adenocarcinoma, gastric cardia carcinoma, tumor, second primary cancer

We recently suggested that there are both pragmatic and normative reasons to classify pregnancy as a disease. Several scholars argued against our claims. In this response, we defend the disease view of pregnancy against their criticism. We claim that the dysfunctional account of disease that some of our critics rely on has some counterintuitive results. Furthermore, we claim that our critics assume what needs to be argued that the primary function of our sexual organs is to reproduce. Since only a small percentage of sexual intercourse leads to pregnancy, it is far from obvious that reproduction is the primary biological function of our sexual organs. We also claim that while taking pregnancy itself as a reference class could avoid the conclusion that pregnancy is a disease, the strategy is problematic since it renders the Boorsean approach to disease and health circular and effectively deprives it of any utility in determining whether a particular phenomenon is a disease or not., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

In 1975, The New England Journal of Medicine published James Rachels' article 'Active and Passive Euthanasia'. The argumentative method that Rachels introduced, the Bare Difference Argument (also known as the Contrast Strategy), became one of the most widely used tools in ethical reasoning. The argument, however, fails to show active euthanasia being morally permissible. It fails because Rachels takes the intuitions from the case where letting die is morally impermissible and applies the intuitions to cases where letting die is morally permissible. While it is possible to create thought-experiments that are more analogous to euthanasia, in this respect, than Rachels' cases, they too are disanalogous to euthanasia with some of the relevant features. Creating the perfect analogy, however, would be a mistake too. Such a case would be too analogous; people would simply be divided on what kind of moral intuitions they would have. The problem thus highlights a methodological limit in philosophical bioethics and raises questions related to the roles of philosophical ethicists in the context of assisted dying., (© 2024 The Author(s). Bioethics published by John Wiley & Sons Ltd.)

Background and Objectives: Large-scale genome-wide studies of chronic hydrocephalus have been lacking. We conducted a genome-wide association study (GWAS) in normal pressure hydrocephalus (NPH)., Methods: We used a case-control study design implementing FinnGen data containing 473,691 Finns with genotypes and nationwide health records. Patients with NPH were selected based on ICD-10 G91.2 diagnosis. To select patients with idiopathic NPH (iNPH) for sensitivity analysis, we excluded patients with a potentially known etiology of the condition using an algorithm on their disease history. The controls were the remaining non-hydrocephalic participants. For a replication analysis, the NPH cohort from UK Biobank (UKBB) was used., Results: We included 1,522 patients with NPH (mean age 72.2 years, 53% women) and 451,091 controls (mean age 60.5 years, 44% women). In the GWAS comparing patients with NPH with the controls, we identified 6 gene regions significantly ( p < 5.0e-8) associated with NPH that replicated in a meta-analysis with UKBB (NPH n = 173). The top loci near the following genes were rs7962263, SLCO1A2 (odds ratio [OR] 0.71, 95% CI 0.65-0.78, p = 1.0e-14); rs798495, AMZ1 / GNA12 (OR 1.29, 95% CI 1.20-1.39, p = 2.9e-12); rs10828247, MLLT10 (OR 0.77, 95% CI 0.71-0.83, p = 1.5e-11); rs561699566 and rs371919113, CDCA2 (OR 0.76, 95% CI 0.70-0.82, p = 1.5e-11); rs56023709, C16orf95 (OR 1.24, 95% CI 1.16-1.33, p = 3.0e-9); and rs62434144, PLEKHG1 (OR 1.23, 95% CI 1.14-1.32, p = 1.4e-8). In the sensitivity analysis comparing only patients with iNPH (n = 1,055) with the controls (n = 451,091), 4 top loci near the following genes remained significant: rs7962263, SLCO1A2 (OR 0.70, 95% CI 0.63-0.78, p = 2.1e-11); rs10828247, MLLT10 (OR 0.74, 95% CI 0.62-0.82, p = 4.6e-10); rs798511, AMZ1 / GNA12 (OR 1.28, 95% CI 1.17-1.39, p = 1.7e-8); and rs56023709, C16orf95 (OR 1.28, 95% CI 1.17-1.39, p = 1.7e-8)., Discussion: We identified 6 loci significantly associated with NPH in the thus far largest GWAS in chronic hydrocephalus. The genes near the top loci have previously been associated with blood-brain barrier and blood-CSF barrier function and with increased lateral brain ventricle volume. The effect sizes and allele frequencies remained similar in NPH and iNPH cohorts, indicating the identified loci are risk determinants for iNPH and likely not explained by associations with other etiologies. However, the exact role of these loci is still unknown, warranting further studies.

Andrea Bidoli argues that ectogestation could be seen as an emancipatory intervention for women. Specifically, she claims that ectogestation would create unique conditions to reevaluate one's reproductive preference, address certain specific negative social implications of gestation and childbirth, and that it is unfair to hold ectogestation to a higher standard than other innovations such as modern contraceptives and non-medical egg freezing. In this commentary, I claim that Bidoli-like so many others-unjustly bypasses men and their reproductive desires. For a long time, the discussion of the ethics of ectogenesis has focused on women and their reproductive liberation. However, since in many countries, an increasing number of men in reproductive age face difficulties in finding a partner and lack access to other forms of assisted reproduction, it is men who need ectogestation the most., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

García-Barranquero et al explore the desirability of human ageing. They differentiate between chronological and biological views of ageing and contend that the positive aspects of ageing are solely linked to chronological ageing. Consequently, the authors embrace the potential for technological interventions in biological ageing. Contrary to their stance, I argue that there are sometimes desirable aspects associated with biological ageing. Therefore, proposals aiming to eliminate, mitigate or diminish biological ageing are not without problems., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Atrial fibrillation is the most common arrhythmia to occur after cardiac surgery, with an incidence of 10% to 50%. It is associated with postoperative complications including increased risk of stroke, prolonged hospital stays and increased costs. Despite new insights into the mechanisms of atrial fibrillation, no specific etiologic factor has been identified as the sole perpetrator of the arrhythmia. Current evidence suggests that the pathophysiology of atrial fibrillation in general, as well as after cardiac surgery, is multifactorial. Studies have also shown that new-onset postoperative atrial fibrillation following cardiac surgery is associated with a higher risk of short-term and long-term mortality. Furthermore, it has been demonstrated that prophylactic medical therapy decreases the incidence of postoperative atrial fibrillation after cardiac surgery. Of note, the incidence of postoperative atrial fibrillation has not changed during the last decades despite the numerous preventive strategies and operative techniques proposed, although the perioperative and postoperative care of cardiac patients as such has improved., Competing Interests: Disclosure: The authors declare no conflict of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Herjeet Kaur Marway recently proposed the Principle of Procreative Justice, which says that reproducers have a strong moral obligation to avoid completing race and colour injustices through their selection choices. In this article, we analyze this principle and argue, appealing to a series of counterexamples, that some of the implications of Marway's Principle of Procreative Justice are difficult to accept. This casts doubt on whether the principle should be adopted. Also, we show that there are some more principled worries regarding Marway's idea of a strong pro tanto duty not to complete injustices through one's procreative choices. Nonetheless, we believe Marway's arguments point in the right general direction regarding duties and structural injustice. Thus, in the final part, we suggest a positive proposal on how it would be possible to respond to the cases we raise. More specifically, we explore the suggestion that agents have a pro tanto duty to participate in eliminating structural injustice. Importantly, this duty can be satisfied, not only in procreation choices but in multiple ways., (© 2024 John Wiley & Sons Ltd.)

Background and study aims Upper gastrointestinal endoscopy (EGD) is one of the most common diagnostic procedures done to examine the foregut, but it can also be used for therapeutic interventions. The main objectives of this study were to investigate trends in EGD utilization and mortality related to it in a national low-threshold healthcare system, assess perioperative safety, and identify and describe patient-reported malpractice claims from the national database. Patients and methods We retrospectively identified patients from the Finnish Patient Care Registry who underwent diagnostic or procedural EGD between 2010 and 2018. In addition, patient-reported claims for malpractice were analyzed from the National Patient Insurance Center (PIC) database. Patient survival data were gathered collectively from the National Death Registry from Statistics Finland. Results During the study period, 409,153 EGDs were performed in Finland for 298,082 patients, with an annual rate of 9.30 procedures per 1,000 inhabitants, with an annual increase of 2.6%. Thirty-day all-cause mortality was 1.70% and 90-day mortality was 3.84%. For every 1,000 patients treated, 0.23 malpractice claims were filed. Conclusions The annual rate of EGD increased by 2.6% during the study, while the rate of interventional procedures remained constant. Also, while the 30-day mortality rate declined over the study period, it is an unsuitable quality metric for EGDs in comprehensive centers because a patient's underlying disease plays a larger role than the procedure in perioperative mortality. Finally, there were few malpractice claims, with self-evident causes prevailing., Competing Interests: Conflict of Interest N.N: none, T.J: none, E.R: none, N.Z: none, J.R: none, S.S.: none, V.K: none, I.I: Surgical Intuitive (travel reimbursement), grants from the government of Finland that were granted to Helsinki University Hospital during the conduct of the study., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial-License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Alterations in microRNA (miRNA) expression have been reported in different cancers. We assessed the expression of 754 oncology-related miRNAs in esophageal adenocarcinoma (EAC) samples and evaluated their correlations with clinical parameters. We found that miR-221 and 483-3p were consistently upregulated in EAC patients vs. controls (Wilcoxon signed-rank test: miR-221 p < 0.0001; miR-483-3p p < 0.0001). Kaplan-Meier analysis showed worse cancer-related survival among all EAC patients expressing high miR-221 or miR-483-3p levels (log-rank p = 0.0025 and p = 0.0235, respectively). Higher miR-221 or miR-483-3p levels also correlated with advanced tumor stages (Mann-Whitney p = 0.0195 and p = 0.0085, respectively), and overexpression of miR-221 was associated with worse survival in low-risk EAC patients. Moreover, a significantly worse outcome was associated with the combined overexpression of miR-221 and miR-483-3p (log-rank p = 0.0410). To identify target genes affected by miRNA overexpression, we transfected the corresponding mimic RNA (miRVANA) for either miR-221 or miR-483-3p in a well-characterized esophageal adenocarcinoma cell line (OE19) and performed RNA-seq analysis. In the miRNA-overexpressing cells, we discovered a convergent dysregulation of genes linked to apoptosis, ATP synthesis, angiogenesis, and cancer progression, including a long non-coding RNA associated with oncogenesis, i.e., MALAT1. In conclusion, dysregulated miRNA expression, especially overexpression of miR-221 and 483-3p, was found in EAC samples. These alterations were connected with a lower cancer-specific patient survival, suggesting that these miRNAs could be useful for patient stratification and prognosis.

In this paper, we identify some key features of what makes something a disease, and consider whether these apply to pregnancy. We argue that there are some compelling grounds for regarding pregnancy as a disease. Like a disease, pregnancy affects the health of the pregnant person, causing a range of symptoms from discomfort to death. Like a disease, pregnancy can be treated medically. Like a disease, pregnancy is caused by a pathogen, an external organism invading the host's body. Like a disease, the risk of getting pregnant can be reduced by using prophylactic measures. We address the question of whether the 'normality' of pregnancy, its current necessity for human survival, or the value often attached to it are reasons to reject the view that pregnancy is a disease. We point out that applying theories of disease to the case of pregnancy, can in many cases illuminate inconsistencies and problems within these theories. Finally, we show that it is difficult to find one theory of disease that captures all paradigm cases of diseases, while convincingly excluding pregnancy. We conclude that there are both normative and pragmatic reasons to consider pregnancy a disease., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)