Assessment of the first presentations of common variable immunodeficiency in a large cohort of patients.

BACKGROUND: Common Variable Immunodeficiency (CVID) is a primary immunodeficiency syndrome resulting in recurrent infections, autoimmunity, and granulomatous manifestations. METHODS AND MATERIALS: This retrospective study was conducted on an Iranian national registry of immunodeficient patients from 2010 to 2021. The frequency of first presentations of CVID and its association with sex, age of onset, and family history of CVID was evaluated. RESULTS: A total of 383 patients entered the study, 164 of whom were female, and the rest were male. The mean age of the patients was 25.3 ± 14.5 years. The most frequent first presentations of CVID were pneumonia (36.8%) and diarrhea (19.1%). Patient sex, age of onset, and family history did not make significant differences in first presentations of this disease. CONCLUSION: pneumonia is the most common first presentation of CVID. Family history of CVID, the age of symptom onset, and sex made no differences in the first presentations of CVID.

Assessment of autoantibodies in paediatric population with primary immunodeficiencies: a pilot study.

BACKGROUND: The correlation between primary immunodeficiencies (PIDs) and autoimmunity shows ethnic and geographical diversity. The aim of our study was to accumulate more data in paediatric PID population. METHODS: 58 children aged 1-17 and with PID (study group) and 14 age-matched immunocompetent individuals (control group) were included in the study. Serum levels of 17 different specific IgG antibodies against autoantigens were measured by means of a quantitative enzyme immunoassay. Immunoglobulin levels were analysed in relation to a detailed medical examination. RESULTS: Autoantibodies against one or more antigens were detected in the sera of 24.14% (n = 14) subjects in the study group. The most frequent were anti-thyroid peroxidase (anti-TPO) antibodies (n = 8; 13.8%). Anti-TPO antibody levels were elevated more often in PID patients with a positive family history of autoimmune diseases (p = 0.04). The screening for anti-deamidated gliadin peptide (DGP) and anti-tissue transglutaminase (tTG) antibodies in our series allowed identifying two previously undiagnosed cases of coeliac disease in PID patients. There was no statistically significant difference between the study and the control group in terms of the autoantibodies prevalence. CONCLUSIONS: This study provides data on the prevalence of autoantibodies in paediatric population diagnosed with PID. Selected autoantibodies (i.e. anti-tTG, anti-DGP) might be useful for the screening of PID to avoid the delay of diagnosis of an autoimmune disease.

CTLA4-Linked Autoimmunity in the Pathogenesis of Endometriosis and Related Infertility: A Systematic Review.

Several studies, although with conflicting results, have sought to determine the concentration of soluble CTLA4 antigens in peripheral blood plasma and peritoneal fluid in patients with endometriosis-related infertility. A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) through a search of the following databases: MEDLINE, EMBASE, Global Health, The Cochrane Library, Health Technology Assessment Database and Web of Science, and Clinical Trials research register. We included observational or prospective human and animal studies with any features related to endometriosis and/or infertility studies involving CTLA4-related pathogenesis published in English. The results of studies in which the size and characteristics of the observed groups were not stated were excluded. From the initial pool of 73 publications identified and screened, we finally included 5 articles to summarize the most recent knowledge about CTLA4-linked autoimmunity in the pathogenesis of endometriosis and related infertility. Evidence from clinical studies shows that CTLA4-based autoimmunity is involved in the maintenance of chronic inflammation in the peritoneal environment, with pre-clinical evidence of anti-CTLA antibodies as a potential novel target therapy for endometriosis. However, CTLA4 gene analyses do not support findings of CTLA4-linked autoimmunity as a primary determinant of the pathogenesis of endometriosis. These findings underlie the role of complex interactions within the family of immune checkpoint molecules involved. Further studies are needed to investigate the clinical relevance of anti-CTLA target therapy, taking into account the potential adverse events and repercussions of novel immunologic therapy modalities. However, with the general scarcity of studies investigating this topic, the clinical importance of CTLA4 autoimmunity still remains unclear.

Assessment of Neuroendocrine Changes and Hypothalamo-Pituitary Autoimmunity in Patients with COVID-19.

SARS-CoV-2 may affect the hypothalamic-pituitary axis and pituitary dysfunction may occur. Therefore, we investigated neuroendocrine changes, in particular, secondary adrenal insufficiency, using a dynamic test and the role of autoimmunity in pituitary dysfunction in patients with COVID-19. The single-center, prospective, case-control study included patients with polymerase chain reaction (PCR)-confirmed COVID-19 and healthy controls. Basal hormone levels were measured, and the adrenocorticotropic hormone (ACTH) stimulation test was performed. Antipituitary (APA) and antihypothalamic antibodies (AHA) were also determined. We examined a total of 49 patients with COVID-19 and 28 healthy controls. The frequency of adrenal insufficiency in patients with COVID-19 was found as 8.2%. Patients with COVID-19 had lower free T3, IGF-1, and total testosterone levels, and higher cortisol and prolactin levels when compared with controls. We also demonstrated the presence of APA in three and AHA in one of four patients with adrenal insufficiency. In conclusion, COVID-19 may result in adrenal insufficiency, thus routine screening of adrenal functions in these patients is needed. Endocrine disturbances in COVID-19 are similar to those seen in acute stressful conditions or infections. Pituitary or hypothalamic autoimmunity may play a role in neuroendocrine abnormalities in COVID-19.

Encefalitis de Von Economo / Von Economo Encephalitis

Introducción: Constantin von Economo reportó en 1917 múltiples casos de manifestaciones neurológicas secundarias a la pandemia de la gripe española, clasificándolos en tres grandes grupos: forma somnolienta-oftalmopléjica, mutismo y la hipercinética, con secuelas similares a la enfermedad de Parkinson. Objetivo: presentar un caso de reciente aparición de patología rara en Cali, Colombia con manejo adecuado en unidad de cuidados intensivos (UCI). Presentación del caso: paciente de 9 años con disminución de la fuerza en extremidades, disartria y somnolencia, que inició deterioro neurológico progresivo requiriendo manejo en UCI. El equipo multidisciplinario diagnosticó encefalitis letárgica e iniciaron manejo con plasmaféresis e inmunosupresión con mejoría significativa. Discusión y conclusiones: como la prevalencia es escasa, el diagnóstico exige un alto índice de sospecha como la ocurrencia de un cuadro infeccioso previo al inicio de los síntomas, ya que se considera una reacción autoinmune cruzada contra antígenos de la sustancia nigra. En algunos casos hay alteraciones en los estudios imagenológicos o en citoquímico de líquido cefalorraquídeo. El manejo con pulsos de metilprednisolona y filtración de plasma con plasmaféresis brinda mejoría significativa con disminución de las secuelas a futuro.

Introduction: In 1917, Constantin von Economo reported multiple cases of neurological manifestations secondary to the Spanish flu pandemic. He classified them into three main clinical forms: somnolent-ophthalmoplegic, mutism and hyperkinetic, causing sequelae resembling Parkinson ́s disease. Objective: to present a case of a recent appearance rare disease entity, in Cali Colombia, receiving appropriate management in the Intensive Care Unit (ICU). Case presentation: 9-year-old patient presenting with limb muscle weakness, dysarthria and somnolence, evidencing progressive neurological deterioration requiring admission to the ICU for management. A diagnosis of encephalitis lethargica (EL) was made by the attending multidisciplinary team and management with plasmapheresis and immunosuppression was started, obtaining significant improvement. Discussion and conclusions: as the prevalence is low, the diagnosis requires a high level of suspicion in cases presenting with infectious conditions prior to the development of symptoms, since it is considered an autoimmune cross-reaction against substantia nigra antigens. Alterations in brain imaging or in cerebrospinal fluid cytometry may be found in some cases. Management with methylprednisolone pulse therapy and filtration plasmapheresis provides significant improvement with a decrease in future sequelae.

The Feasibility and Applicability of Stem Cell Therapy for the Cure of Type 1 Diabetes.

Stem cell therapy using islet-like insulin-producing cells derived from human pluripotent stem cells has the potential to allow patients with type 1 diabetes to withdraw from insulin therapy. However, several issues exist regarding the use of stem cell therapy to treat type 1 diabetes. In this review, we will focus on the following topics: (1) autoimmune responses during the autologous transplantation of stem cell-derived islet cells, (2) a comparison of stem cell therapy with insulin injection therapy, (3) the impact of the islet microenvironment on stem cell-derived islet cells, and (4) the cost-effectiveness of stem cell-derived islet cell transplantation. Based on these various viewpoints, we will discuss what is required to perform stem cell therapy for patients with type 1 diabetes.

Sex hormones, autoimmunity and gender disparity in COVID-19.

The Coronavirus disease 2019 (COVID-19) pandemic has majorly contributed to massive and widespread mortality. Epidemiological data strongly indicates a sex-based disparity in COVID-19 clinical outcomes, with women having lower infection and hospitalisation rates, coupled with better prognosis and lesser mortality. This disparity may be explained by several mechanisms including differences in innate and adaptive immune responses, genetic factors, and an interplay between sex hormones and immune effectors, as well as gender-specific behaviour differences. These pathways, particularly the immunological divergence in response to viral infection, could potentially influence not only COVID-19 pathogenesis and disease course, but also the response to antiviral drugs and vaccines. Furthermore, factors that confer a protective advantage against COVID-19 may be exploited to develop therapeutic strategies to improve clinical outcomes in COVID-19.

Thyroid autoimmunity is associated with higher risk of premature ovarian insufficiency-a nationwide Health Insurance Research Database study.

STUDY QUESTION: Is thyroid autoimmunity associated with a higher risk of low ovarian reserve and POI? SUMMARY ANSWER: Thyroid autoimmunity significantly increases the risk of POI in women. WHAT IS KNOWN ALREADY: POI is closely related with autoimmune disease, and according to some studies, thyroid autoimmunity (TAI) may account for diminished ovarian reserve. However, no large-scale cohort study has demonstrated the association between TAI and POI. STUDY DESIGN, SIZE, DURATION: A longitudinal population-based retrospective cohort study on the National Health Insurance Research Database (NHIRD) was designed. Since 1 March 1995, the National Health Insurance (NHI) programme in Taiwan has included 99.9% of the 23 million population of Taiwan. Patients between 1 January 2000 and 31 December 2012 were eligible for recruitment, and 21 325 subjects were analysed in our study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Two cohorts, Hashimoto's and Grave's disease, were composed of patients with autoimmune thyroid disease between 20 and 40 years of age. The comparison cohorts consisted of patients in the NHIRD without autoimmune thyroid disease matched by age at a ratio of 1:4 in subject numbers. MAIN RESULTS AND THE ROLE OF CHANCE: The Hashimoto's disease (HD) cohort, Grave's disease (GD) cohort and two comparison cohorts were followed up until a diagnosis of amenorrhoea, menopausal syndrome, other ovarian failure or infertility due to ovarian failure had been made. Compared statistically with the non-HD cohort, patients with HD exhibited an 89% higher risk of amenorrhoea (95% CI =1.36-2.61). The HD patients exhibited a 2.40-fold higher risk of infertility due to ovarian failure than the non-HD subjects (hazard ratio (HR)=2.40, 95% confidence interval (CI)=1.02-5.68). In comparison with the non-GD cohort, patients with GD exhibited a 68% higher risk of amenorrhoea (95% CI = 1.43-1.98) after adjustment. According to the Kaplan-Meier analysis, the cumulative incidence of amenorrhoea and menopausal syndrome was significantly higher in the TAI groups than in the control groups. LIMITATIONS, REASONS FOR CAUTION: This is a retrospective study using ICD-9 disease code analysis to determine the statistical association between two diseases. WIDER IMPLICATIONS OF THE FINDINGS: Given that autoimmune thyroid disease is highly associated with early diminished ovarian reserve or even premature ovarian failure or POI, the options for infertility treatment may be re-directed to more efficient methods in infertile patients diagnosed with the disease. If the ovarian reserve is normal at the time of diagnosis of thyroid autoimmune disease, close follow-up of ovarian reserve may be highly recommended. STUDY FUNDING/COMPETING INTEREST(S): This study is supported in part by Taiwan Ministry of Health and Welfare Clinical Trial Center, Grant Number: MOHW109-TDU-B-212-114004. The authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER: N/A.

Paying a Price Twice: Dose-Dependent Effects of Treg Cell-Derived TGF- ß on Tolerance.

Although many immune cells can secrete TGF-ß, whether all sources of TGF-ß are functionally equivalent is unknown. In this issue, Turner et al. uncover the importance of T regulatory (Treg) cell-intrinsic Tgfb1 gene dose in the prevention of autoimmunity and allergic disease.

Assessment of the simultaneous effect of hypothyroidism and thyroid autoimmunity with gestational diabetes on the incidence of type 2 diabetes.

INTRODUCTION: Despite the evidence available on the adverse impact of gestational diabetes (GDM) and thyroid disorders on developing type 2 diabetes (T2DM), the concurrent influence of these disorders on the incidence of T2DM has not been reported yet. METHODS: In this prospective study, 1894 non-diabetic women aged 20 to 60 years, with a history of at least one term delivery, without diagnosed hyperthyroidism were selected at the initiation of the Tehran Thyroid Study (TTS). Pooled logistic regression analyses were used to investigate the association of GDM, thyroid disorders i.e., hypothyroidism and/or thyroid peroxidase antibody (TPOAb) positivity and interaction between GDM and thyroid disorders with the risk of incident T2DM. RESULTS: Of the 1894 participants of the present study, 346 (18.3%) had a history of GDM, and 832 (43.9%) had thyroid disorders. The total cumulative incidence rate of T2DM at the median follow-up time of ~ 12 years was overall 12/1000 person-years (95% confidence interval (CI): 10/1000-13/1000), with an incidence rate of 16/1000 (95%CI: 13/1000-20/1000) in women with GDM; and 11/100,000 (95%CI: 9/100,000-12/1000) among those without GDM. After adjustment for age, the risk of incident T2DM increased among individuals with the previous GDM compared to women without a history of GDM (odds ratio (OR): 1.54, 95%CI: 1.06, 2.25). No significant associations were found between either thyroid disorders or the interaction between GDM and thyroid disorders with the development of T2DM; (OR: 1.14, 95%CI: 0.82, 1.58) and (OR: 1.27, 95%CI: 0.66, 2.43), respectively. CONCLUSION: GDM and thyroid disorders have no concurrent impacts on the incidence of T2DM.

Single-Cell Sequencing of T cell Receptors: A Perspective on the Technological Development and Translational Application.

T cells recognize peptides bound to major histocompatibility complex (MHC) class I and class II molecules at the cell surface. This recognition is accomplished by the expression of T cell receptors (TCR) which are required to be diverse and adaptable in order to accommodate the various and vast number of antigens presented on the MHCs. Thus, determining TCR repertoires of effector T cells is necessary to understand the immunological process in responding to cancer progression, infection, and autoimmune development. Furthermore, understanding the TCR repertoires will provide a solid framework to predict and test the antigen which is more critical in autoimmunity. However, it has been a technical challenge to sequence the TCRs and provide a conceptual context in correlation to the vast number of TCR repertoires in the immunological system. The exploding field of single-cell sequencing has changed how the repertoires are being investigated and analyzed. In this review, we focus on the biology of TCRs, TCR signaling and its implication in autoimmunity. We discuss important methods in bulk sequencing of many cells. Lastly, we explore the most pertinent platforms in single-cell sequencing and its application in autoimmunity.

The prospects of single-cell analysis in autoimmunity.

In the last decade, there has been a tremendous development of technologies focused on analysing various molecular attributes in single cells, with an ever-increasing number of parameters becoming available at the DNA, RNA and protein levels. Much of this progress has involved cells in suspension, but also in situ analysis of tissues has taken great leaps. Paralleling the development in the laboratory, and because of increasing complexity, the analysis of single-cell data is also constantly being updated with new algorithms and analysis platforms. Our immune system shares this complexity, and immunologists have therefore been in the forefront of this technological development. These technologies clearly open new avenues for immunology research, maybe particularly within autoimmunity where the interaction between the faulty immune system and the thymus or the target organ is important. However, the technologies currently available can seem overwhelming and daunting. The aim of this review is to remedy this by giving a balanced overview of the prospects of using single-cell analysis in basal and clinical autoimmunity research, with an emphasis on endocrine autoimmunity.

Identification of Subclinical Lung Involvement in ACPA-Positive Subjects through Functional Assessment and Serum Biomarkers.

Lung involvement is related to the natural history of anti-citrullinated proteins antibodies (ACPA)-positive rheumatoid arthritis (RA), both during the pathogenesis of the disease and as a site of disease-related injury. Increasing evidence suggests that there is a subclinical, early lung involvement during the course of the disease, even before the onset of articular manifestations, which can potentially progress to a symptomatic interstitial lung disease. To date, reliable, non-invasive markers of subclinical lung involvement are still lacking in clinical practice. The aim of this study is to evaluate the diagnostic potential of functional assessment and serum biomarkers in the identification of subclinical lung involvement in ACPA-positive subjects. Fifty ACPA-positive subjects with or without confirmed diagnosis of RA (2010 ARC-EULAR criteria) were consecutively enrolled. Each subject underwent clinical evaluation, pulmonary function testing (PFT) with assessment of diffusion lung capacity for carbon monoxide (DLCO), cardiopulmonary exercise testing (CPET), surfactant protein D (SPD) serum levels dosage and high-resolution computed tomography (HRCT) of the chest. The cohort was composed of 21 ACPA-positive subjects without arthritis (ND), 10 early (disease duration < 6 months, treatment-naïve) RA (ERA) and 17 long-standing (disease duration < 36 months, on treatment) RA (LSRA). LSRA patients had a significantly higher frequency of overall HRCT abnormalities compared to the other groups (p = 0.001). SPD serum levels were significantly higher in ACPA-positive subjects compared with healthy controls (158.5 ± 132.3 ng/mL vs 61.27 ± 34.11 ng/mL; p < 0.0001) and showed an increasing trend from ND subjects to LSRD patients (p = 0.004). Patients with HRCT abnormalities showed significantly lower values of DLCO (74.19 ± 13.2% pred. vs 131.7 ± 93% pred.; p = 0.009), evidence of ventilatory inefficiency at CPET and significantly higher SPD serum levels compared with subjects with no HRCT abnormalities (213.5 ± 157.2 ng/mL vs 117.7 ± 157.3 ng/mL; p = 0.018). Abnormal CPET responses and higher SPD levels were also associated with specific radiological findings. Impaired DLCO and increased SPD serum levels were independently associated with the presence of HRCT abnormalities. Subclinical lung abnormalities occur early in RA-associated autoimmunity. The presence of subclinical HRCT abnormalities is associated with several functional abnormalities and increased SPD serum levels of SPD. Functional evaluation through PFT and CPET, together with SPD assessment, may have a diagnostic potential in ACPA-positive subjects, contributing to the identification of those patients to be referred to HRCT scan.

Assessment of Thymic Output Dynamics After in utero Infection of Mice With Coxsackievirus B4.

The thymus is the main organ of the lymphatic system, in which T cells undergo a rigorous selection to ensure that their receptors (TCRs) will be functional and will not react against the self. Genes encoding for TCR chains are fragmented and must be rearranged by a process of somatic recombination generating TCR rearrangement excision circles (TRECs). We recently documented coxsackievirus B4 (CV-B4) infection of Swiss albino mouse thymus in the course of in utero transmission. In the current study, we intended to evaluate thymic output in this experimental model. For this purpose, pregnant Swiss albino mice were inoculated with CV-B4 at day 10 or 17 of gestation, and thymus and spleen were sampled from offspring at different time points and then subjected to quantification of TREC molecules and Ptk7 gene expression. Results showed a pronounced effect of in utero CV-B4 infection on the thymus with an increase in the cellularity and, consequently, the weight of the organ. sj and DßTREC analysis, by real-time PCR, revealed a significant decrease following CV-B4 infection compared to controls, a decrease which gets worse as time goes by, both in the thymus and in the periphery. Those observations reflect a disturbance in the export of T cells to the periphery and their accumulation within the thymus. The evaluation of Ptk7 transcripts in the thymus, for its part, showed a decrease in expression, especially following an infection at day 10 of gestation, which supports the hypothesis of T cell accumulation in a mature stage in the thymus. The various effects observed correlate either negatively or positively with the viral load in the thymus and spleen. Disruption in thymic export may indeed interfere with T cell maturation. We speculate that this may lead to a premature release of T cells and the possibility of circulating autoreactive or proliferation-impaired T cell clones.

Socioeconomic Position and Incidence of Glomerular Diseases.

BACKGROUND AND OBJECTIVES: Social deprivation is a recognized risk factor for undifferentiated CKD; however, its association with glomerular disease is less well understood. We sought to investigate the relationship between socioeconomic position and the population-level incidence of biopsy-proven glomerular diseases. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this retrospective cohort study, a provincial kidney pathology database (2000-2012) was used to capture all incident cases of membranous nephropathy (n=392), IgA nephropathy (n=818), FSGS (n=375), ANCA-related GN (ANCA-GN, n=387), and lupus nephritis (n=389) in British Columbia, Canada. Quintiles of area-level household income were used as a proxy for socioeconomic position, accounting for regional differences in living costs. Incidence rates were direct standardized to the provincial population using census data for age and sex and were used to generate standardized rate ratios. For lupus nephritis, age standardization was performed separately in men and women. RESULTS: A graded increase in standardized incidence with lower income was observed for lupus nephritis (P<0.001 for trend in both sexes) and ANCA-GN (P=0.04 for trend). For example, compared with the highest quintile, the lowest income quintile had a standardized rate ratio of 1.7 (95% confidence interval, 1.19 to 2.42) in women with lupus nephritis and a standardized rate ratio of 1.5 (95% confidence interval, 1.09 to 2.06) in ANCA-GN. The association between income and FSGS was less consistent, in that only the lowest income quintile was associated with a higher incidence of disease (standardized rate ratio, 1.55; 95% confidence interval, 1.13 to 2.13). No significant associations were demonstrated for IgA nephropathy or membranous nephropathy. CONCLUSIONS: Using population-level data and a centralized pathology database, we observed an inverse association between socioeconomic position and the standardized incidence of lupus nephritis and ANCA-GN.

Rationale for enteroviral vaccination and antiviral therapies in human type 1 diabetes.

In type 1 diabetes, pancreatic beta cells are destroyed by chronic autoimmune responses. The disease develops in genetically susceptible individuals, but a role for environmental factors has been postulated. Viral infections have long been considered as candidates for environmental triggers but, given the lack of evidence for an acute, widespread, cytopathic effect in the pancreas in type 1 diabetes or for a closely related temporal association of diabetes onset with such infections, a role for viruses in type 1 diabetes remains unproven. Moreover, viruses have rarely been isolated from the pancreas of individuals with type 1 diabetes, mainly (but not solely) due to the inaccessibility of the organ. Here, we review past and recent literature to evaluate the proposals that chronic, recurrent and, possibly, persistent enteroviral infections occur in pancreatic beta cells in type 1 diabetes. We also explore whether these infections may be sustained by different virus strains over time and whether multiple viral hits can occur during the natural history of type 1 diabetes. We emphasise that only a minority of beta cells appear to be infected at any given time and that enteroviruses may become replication defective, which could explain why they have been isolated from the pancreas only rarely. We argue that enteroviral infection of beta cells largely depends on the host innate and adaptive immune responses, including innate responses mounted by beta cells. Thus, we propose that viruses could play a role in type 1 diabetes on multiple levels, including in the triggering and chronic stimulation of autoimmunity and in the generation of inflammation and the promotion of beta cell dysfunction and stress, each of which might then contribute to autoimmunity, as part of a vicious circle. We conclude that studies into the effects of vaccinations and/or antiviral drugs (some of which are currently on-going) is the only means by which the role of viruses in type 1 diabetes can be finally proven or disproven.

The "Eternal Recurrence" of Arteritis. Suggesting Autoimmunity Underlining Friedrich Nietzsche's Challenging Clinical Case.

Friedrich Wilhelm Nietzsche (Röcken 1844 -Weimar 1900), the philosopher who theorized the concept of "eternal recurrence", suffered a lifelong multifaceted chronic illness that started in pediatric age with severe headaches and ended up with stroke at the age of 56. Even though many hypothetical diagnosis have been proposed in recent years, they all failed to explain the totality of clinical conditions that co-occurred in the philosopher's extremely challenging case, and debate on the matter is still open. In this report, we suggest an autoimmune condition, specifically Takayasu's arteritis, as a possible etiology of the philosopher's illness, which could not only potentially fit all available clinical data but also be the medical counterpart of Nietzsche's philosophical thought: could eternal recurrence of arteritis explain Zarathustra's destiny? If so, could a vascular surgeon, at this time in future, be so superhuman to change it?