Development and prognostic validation of a three-level NHG-like deep learning-based model for histological grading of breast cancer.

BACKGROUND: Histological grade is a well-known prognostic factor that is routinely assessed in breast tumours. However, manual assessment of Nottingham Histological Grade (NHG) has high inter-assessor and inter-laboratory variability, causing uncertainty in grade assignments. To address this challenge, we developed and validated a three-level NHG-like deep learning-based histological grade model (predGrade). The primary performance evaluation focuses on prognostic performance. METHODS: This observational study is based on two patient cohorts (SöS-BC-4, N = 2421 (training and internal test); SCAN-B-Lund, N = 1262 (test)) that include routine histological whole-slide images (WSIs) together with patient outcomes. A deep convolutional neural network (CNN) model with an attention mechanism was optimised for the classification of the three-level histological grading (NHG) from haematoxylin and eosin-stained WSIs. The prognostic performance was evaluated by time-to-event analysis of recurrence-free survival and compared to clinical NHG grade assignments in the internal test set as well as in the fully independent external test cohort. RESULTS: We observed effect sizes (hazard ratio) for grade 3 versus 1, for the conventional NHG method (HR = 2.60 (1.18-5.70 95%CI, p-value = 0.017)) and the deep learning model (HR = 2.27, 95%CI 1.07-4.82, p-value = 0.033) on the internal test set after adjusting for established clinicopathological risk factors. In the external test set, the unadjusted HR for clinical NHG 2 versus 1 was estimated to be 2.59 (p-value = 0.004) and clinical NHG 3 versus 1 was estimated to be 3.58 (p-value < 0.001). For predGrade, the unadjusted HR for predGrade 2 versus 1 HR = 2.52 (p-value = 0.030), and 4.07 (p-value = 0.001) for preGrade 3 versus 1 was observed in the independent external test set. In multivariable analysis, HR estimates for neither clinical NHG nor predGrade were found to be significant (p-value > 0.05). We tested for differences in HR estimates between NHG and predGrade in the independent test set and found no significant difference between the two classification models (p-value > 0.05), confirming similar prognostic performance between conventional NHG and predGrade. CONCLUSION: Routine histopathology assessment of NHG has a high degree of inter-assessor variability, motivating the development of model-based decision support to improve reproducibility in histological grading. We found that the proposed model (predGrade) provides a similar prognostic performance as clinical NHG. The results indicate that deep CNN-based models can be applied for breast cancer histological grading.

ß2-Adrenoreceptor Agonists, Montelukast, and Parkinson Disease Risk.

OBJECTIVE: This study was undertaken to examine the association between montelukast use, ß2-adrenoreceptor (ß2AR) agonist use, and later Parkinson disease (PD). METHODS: We ascertained use of ß2AR agonists (430,885 individuals) and montelukast (23,315 individuals) from July 1, 2005 to June 30, 2007, and followed 5,186,886 PD-free individuals from July 1, 2007 to December 31, 2013 for incident PD diagnosis. We estimated hazard ratios and 95% confidence intervals using Cox regressions. RESULTS: We observed 16,383 PD cases during on average 6.1 years of follow-up. Overall, use of ß2AR agonists and montelukast were not related to PD incidence. A 38% lower PD incidence was noted among high-dose montelukast users when restricted to PD registered as the primary diagnosis. INTERPRETATION: Overall, our data do not support inverse associations between ß2AR agonists, montelukast, and PD. The prospect of lower PD incidence with high-dose montelukast exposure warrants further investigation, especially with adjustment for high-quality data on smoking. ANN NEUROL 2023;93:1023-1028.

Analysis of factors influencing the organizational capacity of Institutional Review Boards In China: a crisp-set Qualitative Comparative Analysis based on 107 cases.

BACKGROUND: Institutional Review Boards (IRBs) play a vital role in safeguarding the rights and interests of both research participants and researchers. However, China initiated the establishment of its own IRB system relatively late in comparison to international standards. Despite commendable progress, there is a pressing need to strengthen the organizational capacity building of Chinese IRBs. Hence, this study aims to analyze the key factors driving the enhancement of organizational capacity within these committees. METHOD: The cross-sectional survey for this research was conducted from July 2020 to January 2022. Following the statistical grouping based on the "2020 China Health Statistical Yearbook", a systematic investigation of IRBs in various provinces of China was carried out. In-depth interviews and questionnaire surveys were conducted with the chairpersons and administrative executives (or secretaries) of highly cooperative IRBs. Subsequently, data were collected from 107 IRBs. Qualitative Comparative Analysis (QCA) was employed as the method to analyze the factors influencing the organizational capacity of medical ethics committees and explore the diverse combinations of these factors. RESULTS: Through a singular necessary condition analysis, the variable "protection of rights and interests" emerges as a critical factor contributing to the robust construction of Institutional Review Boards Institutional Review Boards (IRBs). Conversely, the variables of "lack of member ability, absence of review process, and deficiency in the supervision mechanism" collectively constitute a sufficient condition leading to weaker IRB construction. The state analysis uncovers three interpretation modes: member ability-oriented (M1), system process-oriented mode (M2), and resource system-oriented mode (M3). CONCLUSIONS: The results of this study are effectively explicable using the "Triangular Force" model proposed for the hypothesis of IRBs' organizational capacity, which provides a solid foundation for the development of organizational capabilities in IRBs. To enhance the organizational capacity of IRBs in China, it is imperative to elevate the competence of committee members and strengthen team development. This can be achieved by establishing a comprehensive regulatory framework and refining procedural protocols. Moreover, clarifying the organizational structure and optimizing resource allocation are essential steps in bolstering the overall organizational capabilities of these committees.

Relationship Between Poor Olfaction and Mortality Among Community-Dwelling Older Adults: A Cohort Study.

Background: Poor olfaction is common among older adults and has been linked to higher mortality. However, most studies have had a relatively short follow-up and have not explored potential explanations. Objective: To assess poor olfaction in relation to mortality in older adults and to investigate potential explanations. Design: Community-based prospective cohort study. Setting: 2 U.S. communities. Participants: 2289 adults aged 71 to 82 years at baseline (37.7% black persons and 51.9% women). Measurements: Brief Smell Identification Test in 1999 or 2000 (baseline) and all-cause and cause-specific mortality at 3, 5, 10, and 13 years after baseline. Results: During follow-up, 1211 participants died by year 13. Compared with participants with good olfaction, those with poor olfaction had a 46% higher cumulative risk for death at year 10 (risk ratio, 1.46 [95% CI, 1.27 to 1.67]) and a 30% higher risk at year 13 (risk ratio, 1.30 [CI, 1.18 to 1.42]). Similar associations were found in men and women and in white and black persons. However, the association was evident among participants who reported excellent to good health at baseline (for example, 10-year mortality risk ratio, 1.62 [CI, 1.37 to 1.90]) but not among those who reported fair to poor health (10-year mortality risk ratio, 1.06 [CI, 0.82 to 1.37]). In analyses of cause-specific mortality, poor olfaction was associated with higher mortality from neurodegenerative and cardiovascular diseases. Mediation analyses showed that neurodegenerative diseases explained 22% and weight loss explained 6% of the higher 10-year mortality among participants with poor olfaction. Limitation: No data were collected on change in olfaction and its relationship to mortality. Conclusion: Poor olfaction is associated with higher long-term mortality among older adults, particularly those with excellent to good health at baseline. Neurodegenerative diseases and weight loss explain only part of the increased mortality. Primary Funding Source: National Institutes of Health and Michigan State University.

[Systematic review of the effect of pictorial warnings on cigarette packages in smoking behavior]. / Revisión sistemática del efecto de las advertencias gráficas impresas en los paquetes de cigarrillos sobre el comportamiento de los fumadores.

We used a structured approach to assess whether active smokers presented with pictorial warnings on cigarette packages (PWCP) had a higher probability of quitting, reducing, and attempting to quit smoking than did unexposed smokers. We identified 21 articles from among nearly 2500 published between 1993 and 2013, prioritizing coverage over relevance or quality because we expected to find only a few studies with behavioral outcomes. We found very large heterogeneity across studies, poor or very poor methodological quality, and generally null or conflicting findings for any explored outcome. The evidence for or against the use of PWCP is insufficient, suggesting that any effect of PWCP on behavior would be modest. Determining the single impact of PWCP on behavior requires studies with strong methodological designs and longer follow-up periods.

Systematic review of the effect of pictorial warnings on cigarette packages in smoking behavior.

We used a structured approach to assess whether active smokers presented with pictorial warnings on cigarette packages (PWCP) had a higher probability of quitting, reducing, and attempting to quit smoking than did unexposed smokers. We identified 21 articles from among nearly 2500 published between 1993 and 2013, prioritizing coverage over relevance or quality because we expected to find only a few studies with behavioral outcomes. We found very large heterogeneity across studies, poor or very poor methodological quality, and generally null or conflicting findings for any explored outcome. The evidence for or against the use of PWCP is insufficient, suggesting that any effect of PWCP on behavior would be modest. Determining the single impact of PWCP on behavior requires studies with strong methodological designs and longer follow-up periods.

Mapping the landscape of histomorphological cancer phenotypes using self-supervised learning on unannotated pathology slides.

Cancer diagnosis and management depend upon the extraction of complex information from microscopy images by pathologists, which requires time-consuming expert interpretation prone to human bias. Supervised deep learning approaches have proven powerful, but are inherently limited by the cost and quality of annotations used for training. Therefore, we present Histomorphological Phenotype Learning, a self-supervised methodology requiring no labels and operating via the automatic discovery of discriminatory features in image tiles. Tiles are grouped into morphologically similar clusters which constitute an atlas of histomorphological phenotypes (HP-Atlas), revealing trajectories from benign to malignant tissue via inflammatory and reactive phenotypes. These clusters have distinct features which can be identified using orthogonal methods, linking histologic, molecular and clinical phenotypes. Applied to lung cancer, we show that they align closely with patient survival, with histopathologically recognised tumor types and growth patterns, and with transcriptomic measures of immunophenotype. These properties are maintained in a multi-cancer study.

Self-Supervised Learning Reveals Clinically Relevant Histomorphological Patterns for Therapeutic Strategies in Colon Cancer.

Self-supervised learning (SSL) automates the extraction and interpretation of histopathology features on unannotated hematoxylin-and-eosin-stained whole-slide images (WSIs). We trained an SSL Barlow Twins-encoder on 435 TCGA colon adenocarcinoma WSIs to extract features from small image patches. Leiden community detection then grouped tiles into histomorphological phenotype clusters (HPCs). HPC reproducibility and predictive ability for overall survival was confirmed in an independent clinical trial cohort (N=1213 WSIs). This unbiased atlas resulted in 47 HPCs displaying unique and sharing clinically significant histomorphological traits, highlighting tissue type, quantity, and architecture, especially in the context of tumor stroma. Through in-depth analysis of these HPCs, including immune landscape and gene set enrichment analysis, and association to clinical outcomes, we shed light on the factors influencing survival and responses to treatments like standard adjuvant chemotherapy and experimental therapies. Further exploration of HPCs may unveil new insights and aid decision-making and personalized treatments for colon cancer patients.

Bio-priming of banana tissue culture plantlets with endophytic Bacillus velezensis EB1 to improve Fusarium wilt resistance.

Tissue culture techniques have been routinely used for banana propagation and offered rapid production of planting materials with favorable genotypes and free of pathogenic microorganisms in the banana industry. Meanwhile, extensive scientific work suggests that micropropagated plantlets are more susceptible to Fusarium oxysporum f. sp. cubense (Foc), the deadly strain that causes Fusarium wilt of bananas than conventional planting material due to the loss of indigenous endophytes. In this study, an endophytic bacterium Bacillus velezensis EB1 was isolated and characterized. EB1 shows remarkable in vitro antagonistic activity against Foc with an inhibition rate of 75.43% and induces significant morphological and ultrastructural changes and alterations in the hyphae of Foc. Colony-forming unit (c.f.u.) counting and scanning electron microscopy (SEM) revealed that EB1 could colonize both the surface and inner tissues of banana tissue culture plantlets. Banana tissue culture plantlets of late rooting stage bioprimed with EB1 could efficiently ward off the invasive of Foc. The bio-priming effect could maintain in the acclimatized banana plants and significantly decrease the disease severity of Fusarium wilt and induce strong disease resistance by manipulating plant defense signaling pathways in a pot experiment. Our results provide the adaptability and potential of native endophyte EB1 in protecting plants from pathogens and infer that banana tissue culture plantlets bio-priming with endophytic microbiota could be a promising biological solution in the fight against the Fusarium wilt of banana.

Unraveling the Molecular Mechanisms of Tomatoes' Defense against Botrytis cinerea: Insights from Transcriptome Analysis of Micro-Tom and Regular Tomato Varieties.

Botrytis cinerea is a devastating fungal pathogen that causes severe economic losses in global tomato cultivation. Understanding the molecular mechanisms driving tomatoes' response to this pathogen is crucial for developing effective strategies to counter it. Although the Micro-Tom (MT) cultivar has been used as a model, its stage-specific response to B. cinerea remains poorly understood. In this study, we examined the response of the MT and Ailsa Craig (AC) cultivars to B. cinerea at different time points (12-48 h post-infection (hpi)). Our results indicated that MT exhibited a stronger resistant phenotype at 18-24 hpi but became more susceptible to B. cinerea later (26-48 hpi) compared to AC. Transcriptome analysis revealed differential gene expression between MT at 24 hpi and AC at 22 hpi, with MT showing a greater number of differentially expressed genes (DEGs). Pathway and functional annotation analysis revealed significant differential gene expression in processes related to metabolism, biological regulation, detoxification, photosynthesis, and carbon metabolism, as well as some immune system-related genes. MT demonstrated an increased reliance on Ca2+ pathway-related proteins, such as CNGCs, CDPKs, and CaMCMLs, to resist B. cinerea invasion. B. cinerea infection induced the activation of PTI, ETI, and SA signaling pathways, involving the modulation of various genes such as FLS2, BAK1, CERK1, RPM, SGT1, and EDS1. Furthermore, transcription factors such as WRKY, MYB, NAC, and AUX/IAA families played crucial regulatory roles in tomatoes' defense against B. cinerea. These findings provide valuable insights into the molecular mechanisms underlying tomatoes' defense against B. cinerea and offer potential strategies to enhance plant resistance.

Hepatic depletion of nucleolar protein mDEF causes excessive mitochondrial copper accumulation associated with p53 and NRF1 activation.

Copper is an essential component in the mitochondrial respiratory chain complex IV (cytochrome c oxidases). However, whether any nucleolar factor(s) is(are) involved in regulating the mitochondrial copper homeostasis remains unclear. The nucleolar localized Def-Capn3 protein degradation pathway cleaves target proteins, including p53, in both zebrafish and human nucleoli. Here, we report that hepatic depletion of mDEF in mice causes an excessive copper accumulation in the mitochondria. We find that mDEF-depleted hepatocytes show an exclusion of CAPN3 from the nucleoli and accumulate p53 and NRF1 proteins in the nucleoli. Furthermore, we find that NRF1 is a CAPN3 substrate. Elevated p53 and NRF1 enhances the expression of Sco2 and Cox genes, respectively, to allow more copper acquirement in the mDefloxp/loxp, Alb:Cre mitochondria. Our findings reveal that the mDEF-CAPN3 pathway serves as a novel mechanism for regulating the mitochondrial copper homeostasis through targeting its substrates p53 and NRF1.

Maternal consumption of a fermented diet protects offspring against intestinal inflammation by regulating the gut microbiota.

The neonatal intestinal tract is immature and can be easily infected by pathogens causing inflammation. Maternal diet manipulation is a promising nutritional strategy to enhance the gut health of offspring. A fermented diet is a gut microbiota targeting diet containing live probiotics and their metabolites, which benefit the gut and overall health host. However, it remains unclear how a maternal fermented diet (MFD) affects neonatal intestinal inflammation. Here, in vivo and in vitro models together with multi-omics analysis were applied to investigate the impacts and the underlying mechanism through which an MFD prevents from gut inflammation in neonates. An MFD remarkably improved the performance of both sows and piglets and significantly altered the gut microbiome and milk metabolome of sows. In addition, the MFD significantly accelerated the maturation of the gut microbiota of neonates and increased the abundance of gut Lactobacillus and the microbial functions of amino acid-related enzymes and glucose metabolism on the weaning day. Notably, the MFD reduced susceptibility to colonic inflammation in offspring. The fecal microbiota of sows was then transplanted into mouse dams and it was found that the mouse dams and pups in the MFD group alleviated the LPS-induced decrease in gut Lactobacillus abundance and barrier injury. Milk L-glutamine (GLN) and gut Lactobacillus reuteri (LR) were found as two of the main MFD-induced sow effectors that contributed to the gut health of piglets. The properties of LR and GLN in modulating gut microbiota and alleviating colonic inflammation by inhibiting the phosphorylation of p38 and JNK and activation of Caspase 3 were further verified. These findings provide the first data revealing that an MFD drives neonate gut microbiota development and ameliorates the colonic inflammation by regulating the gut microbiota. This fundamental evidence might provide references for modulating maternal nutrition to enhance early-life gut health and prevent gut inflammation.

Integrated Microbiomic and Metabolomic Dynamics of Fermented Corn and Soybean By-Product Mixed Substrate.

Microbes and their metabolites produced in fermented food have been considered as critical contributors to the quality of the final products, but the comprehensive understanding of the microbiomic and metabolomic dynamics in plant-based food during solid-state fermentation remains unclear. Here, the probiotics of Bacillus subtilis and Enterococcus faecalis were inoculated into corn and defatted soybean to achieve the two-stage solid-state fermentation. A 16S sequencing and liquid chromatography-tandem mass spectrometry were applied to investigate the dynamics of microbiota, metabolites, and their integrated correlations during fermentation. The results showed that the predominant bacteria changed from Streptophyta and Rickettsiales at 0 h to Bacillus and Pseudomonas in aerobic stage and then to Bacillus, Enterococcus, and Pseudomonas in anaerobic stage. In total, 229 notably different metabolites were identified at different fermentation times, and protein degradation, amino acid synthesis, and carbohydrate metabolism were the main metabolic pathways during the fermentation. Notably, phenylalanine metabolism was the most important metabolic pathway in the fermentation process. Further analysis of the correlations among the microbiota, metabolites, and physicochemical characteristics indicated that Bacillus spp. was significantly correlated with amino acids and carbohydrate metabolism in aerobic stage, and Enterococcus spp. was remarkably associated with amino acids metabolism and lactic acid production in the anaerobic stage. The present study provides new insights into the dynamic changes in the metabolism underlying the metabolic and microbial profiles at different fermentation stages, and are expected to be useful for future studies on the quality of fermented plant-based food.

Using deep learning to detect patients at risk for prostate cancer despite benign biopsies.

Routine transrectal ultrasound-guided systematic prostate biopsy only samples a small volume of the prostate and tumors between biopsy cores can be missed, leading to low sensitivity to detect clinically relevant prostate cancers (PCa). Deep learning may enable detection of PCa despite benign biopsies. We included 14,354 hematoxylin-eosin stained benign prostate biopsies from 1,508 men in two groups: men without established PCa diagnosis and men with at least one core biopsy diagnosed with PCa. A 10-Convolutional Neural Network ensemble was optimized to distinguish benign biopsies from benign men or patients with PCa. Area under the receiver operating characteristic curve was estimated at 0.739 (bootstrap 95% CI:0.682-0.796) on man level in the held-out test set. At the specificity of 0.90, the model sensitivity was 0.348. The proposed model can detect men with risk of missed PCa and has the potential to reduce false negatives and to indicate men who could benefit from rebiopsies.

Strategic Choices for Social Responsibility of Startups in China.

This study uses the structure-conduct-performance analytical framework in industrial organization theory to analyze Chinese startups' corporate social responsibility (CSR) assuming normalization after the COVID-19 pandemic. Specifically, we take the external impact of the pandemic on startups during the pandemic as a starting point for analyzing the changes in the structure of startups and their CSR performance. We find a positive correlation between the pandemic and the performance of startups. We propose that the CSR of startups is not simply altruism but must involve an "altruistic and self-interested" mechanism. Therefore, this study proposes that during the pandemic, startups need to rebuild their CSR model. Furthermore, the company's "economic man" and "social man" are interdependent; economic, ethical, and legal responsibilities are parallel and charitable responsibilities remain the highest pursuit amid the pandemic. The social responsibility of startups as the COVID-19 pandemic normalizes is a strategic choice.

Analysis of Literary Situation and Reconstruction of the Writing Subject in Literary Education by Educational Psychology.

Educational psychology focuses on the laws of change in the knowledge, skills, and individual psychology of the educatees in the process of education and teaching. Writing teaching is a key and difficult point in literature teaching. Nowadays, it is common for students to be afraid and tired of writing in school literature education. In view of these problems, the present work optimizes the teaching mode of writing from the perspective of reconstructing the writing subject. Through literature research and interdisciplinary analysis, a questionnaire is designed to analyze the literary situation and the reconstruction of writing subjects in literary education. The questionnaire is aimed at three aspects, namely the hidden educational effect of teachers' personality charm, the influencing factors of students' psychology and students' learning effect, and the influencing factors of psychology of the communication between teachers and students and teachers' teaching effect. Then, the changes of students' performance in literary class in these three aspects before and after using the teaching strategy of writing subject reconstruction are analyzed. Finally, the changes of students' grades in the literary course are investigated. In this experiment, a total of 400 questionnaires were distributed, and a total of 389 questionnaires were collected. The survey results show that the number of students who feel the classroom atmosphere is active increases by 10%, the number of students who listen carefully and take notes increases by 7%, and 45% of students have improved their grades. Besides, after the implementation of the teaching strategy, most students change their attitude to the literature course, become more active, and significantly improve their motivation for learning. This study has a certain reference value for the analysis of literary situations and the reconstruction of writing subjects in literary education from the perspective of educational psychology.

Irritable bowel syndrome and Parkinson's disease risk: register-based studies.

To examine whether irritable bowel syndrome (IBS) was related to the future risk of Parkinson's disease (PD), we conducted a nested case-control study in the Swedish total population including 56,564 PD cases identified from the Swedish Patient Register and 30 controls per case individually matched by sex and year of birth. Odds ratios (ORs) with 95% confidence intervals (CIs) for having a prior diagnosis of IBS were estimated using conditional logistic regression. We furthermore conducted a cohort study using the Swedish Twin Registry following 3046 IBS patients identified by self-reported abdominal symptoms and 41,179 non-IBS individuals. Through Cox proportional hazard models, we estimated hazard ratios (HRs) and 95% CIs for PD risk. In the nested case-control study, 253 (0.4%) PD cases and 5204 (0.3%) controls had a previous IBS diagnosis. IBS diagnosis was associated with a 44% higher risk of PD (OR = 1.44, 95% CI 1.27-1.63). Temporal relationship analyses showed 53% and 38% increased risk of PD more than 5 and 10 years after IBS diagnosis, respectively. In the cohort analysis based on the Swedish Twin Registry, there was no statistically significantly increased risk of PD related to IBS (HR = 1.25, 95% CI = 0.87-1.81). Our results suggest a higher risk of PD diagnosis after IBS. These results provide additional evidence supporting the importance of the gut-brain axis in PD.

Analysis on Entrepreneurship Psychology of Preschool Education Students With Entrepreneurial Intention.

To diversify the creative thinking of preschool education students and improve their ability to innovate and start a business, a survey of preschool education students under entrepreneurial psychology theory was conducted in this research. Based on the theoretical foundation of entrepreneurial psychology, this article analyzed the entrepreneurial psychological quality and psychological education of college students. By investigating preschool education students in a certain college in Sichuan as the research object, the author explored the current entrepreneurial intentions of college students and their entrepreneurial psychological problems. In response to the current entrepreneurial situation of college graduates, relevant countermeasures were proposed from the perspective of the school to support their entrepreneurial psychology. Among the 205 preschool education college students, the students were more willing to give full play to their professional expertise in terms of employment intentions. At the same time, there were still situations in which students were dissatisfied with the prospects of preschool education career development and wanted to achieve the value of life through other approaches. Most students in preschool education had a wait-and-see attitude toward entrepreneurship. Only 35% of students had a clear intention to start a business and made their plans for entrepreneurship. More than 90% of students held that they had developed inadequate entrepreneurial ability, and 80% of students believed that they lacked the required professional knowledge. These two factors constitute the main reasons for students' negative attitudes toward entrepreneurship. Nevertheless, colleges may stimulate the potential of students' self-development through the improvement of entrepreneurial psychological education courses, the construction of psychological consultation institutions on campus, and the establishment of interactive platforms for entrepreneurship. In this way, students' entrepreneurial psychology can be cultivated in an all-round way. Therefore, to deal with the weak overall entrepreneurial consciousness of college students, the colleges should cultivate entrepreneurial innovative talents by strengthening the psychological education of entrepreneurship for students, and help college students achieve entrepreneurial success.

Appendectomy, Tonsillectomy and Parkinson's Disease Risk: A Swedish Register-Based Study.

Introduction: The gut-brain hypothesis proposes that Parkinson's disease (PD) pathology may start in the gut and later spread to the brain in a prion-like manner. As PD pathology is redundant in the appendix and tonsils, which are important gut-associated lymphoid tissues, we examined whether appendectomy and tonsillectomy were associated with later PD risk. Methods: The nested case-control study included 78,650 PD patients born in 1900-1980 and with a diagnosis of PD between 1964 and 2010. For each PD patient, we randomly selected 40 non-PD controls individually matched for sex and year of birth at the date of PD diagnosis. Appendectomy and tonsillectomy before PD diagnosis were ascertained from the Swedish Patient Register from 1964 onward. We calculated odds ratios (OR) with 95% confidence intervals (CI) using conditional logistic regression adjusting for country of birth, highest achieved education, COPD, comorbidity index, and number of hospital visits. Results: Overall, we found 16% lower risk of PD linked to previous appendectomy (OR = 0.84, 95% CI: 0.80-0.88) and 8% lower risk of PD linked to previous tonsillectomy, although not statistically significant (OR = 0.92, 95% CI: 0.81-1.04). A 7 and 15% lower risk of PD was also noted ≥20 years after appendectomy and tonsillectomy, respectively. Similar associations were observed for men and women but were stronger for PD diagnosed after age 60. Conclusion: Appendectomy and potentially also tonsillectomy were associated with a lower risk PD. A potential mechanism may involve surgical removal of alpha-synuclein redundancy in the appendix and tonsils.