Cohort Differences in Swedish Union Membership 1956–2019 and the Role of Individualization

Discussions of the role of cohort differences have long been part of academic research on union membership, with a central hypothesis being that the general decline in unionization is caused by changes toward more individualistic values in the younger generations. However, the short time span of most studies makes it uncertain if they can separate cohort effects from age effects. Using survey data going back to 1956, we test the individualization hypothesis. Our main result is that later Swedish cohorts are indeed less prone to join unions. In particular, the differences between cohorts born before and after ca 1970 are striking. We also provide evidence that the erosion in union membership in Sweden is not related to changes toward more individualistic values in later cohorts, or even to more negative views of unions per se.

Ongoing Symptoms and Reduced Health Measures in Unicentric Castleman Disease Patients Despite Perceived-to-be Curative Surgical Excision

Unicentric Castleman disease (UCD) is one of several subtypes of Castleman disease that share characteristic histopathology. While UCD involves one region of enlarged lymph nodes (LN) and milder symptoms, idiopathic multicentric CD (iMCD) involves multiple regions of enlarged lymph nodes and cytokine-driven organ dysfunction. UCD symptoms can occur due to compression of neighboring structures or inflammatory cytokine production. Complete excision of the enlarged LN is reported in the literature to be curative in 84-96% of UCD patients. However, many UCD patients describe persistence or worsening of symptoms post excision despite normal laboratory values and absence of measurable disease. To better characterize and describe the experience of individuals diagnosed with UCD, we administered surveys to UCD patients to capture information about general quality of life (QOL), specific health measures, and ongoing UCD symptoms. All patients enrolled in the ACCELERATE Natural History registry who either self-reported a UCD diagnosis or were suspected to have a UCD diagnosis were invited to participate in the Rand36-item Short Form survey, the EQ-5D-5L, the MCD Symptom Score survey, all of which are validated instruments, as well as an additional form regarding ongoing symptoms. Among the 107 UCD patients invited to participate, 51 (48%) responded. Descriptive analyses were conducted on all 51 respondents with a self-reported UCD diagnosis. Subsequently, a subset consisting of 25 respondents, who had been reviewed by a panel of physicians that confirmed a UCD diagnosis (confirmed subcohort, CS), was analyzed. Mean (SD) EQ-5D-5L health index score (100 being perfect health, 0 being worst health imaginable) of the 51 patients was 67.6 (19.9), compared to a representative sample of the US population whose score was 80.4. Patients reported having poor health over the prior 4 weeks, with low scores indicating high levels of fatigue (38.8) and poor general health (47.7). These are notable and comparable to scores for fatigue (52.2) and general health (57.0) among a separate cohort of patients with diabetes, hypertension, coronary heart disease, and/or depression. Strikingly, 57% of patients reported continuation of symptoms post-LN excision, with an additional 16% being unsure. Only 29% reported complete symptom resolution, with the remainder reporting partial resolution (29%), stable disease (20%), worsening disease (12%), or unsure (10%). Nearly all 51 respondents underwent their LN-excision >1 year prior (93%). Fatigue (61%) and night sweats (39%) were most commonly reported in patients with continued symptoms. In fact, 27 patients (53%) reported ongoing symptoms on the day of survey completion with 93% of those patients reporting fatigue that day. Of note, sub-group analyses of the CS revealed similar findings, with a potential trend towards slightly better overall health with mean (SD) health index score 72.6 (14.5), fatigue (44%) and night sweats (36%), and ongoing symptoms reported in 40%. Of the patients in the CS, all had a complete resection, with 3 demonstrating subsequent lymphadenopathy in new regions ranging from 6 months to 5 years after their initial excision. Overall, these data suggest that UCD patients who have had resection of disease continue to experience symptoms that affect QOL. Patients reported lower QOL than a representative national average, as well as health measures comparable to a separate cohort of individuals with chronic health conditions. Of note, the full cohort of self-reported individuals consistently reported lower scores compared to the subset of patients with confirmed UCD (not statistically tested). Of the 26 non-confirmed cases, 8 did not achieve criteria to meet UCD and 18 have not yet been reviewed by our physician panel. A different undiagnosed disorder may be the root cause of symptoms in a portion of these patients and others may be experiencing symptoms due to a co-occurring disorder. These results may be confounded by reporting bias and may not be representative of the full UCD population. Nevertheless, these data suggest that perceived-to-be curative excision does not result in symptom-free outcomes in a substantial proportion of patients and that symptom management may be required beyond excision. Future work is needed to correlate these findings with clinical, laboratory, and experimental data to further elucidate mechanisms and treatment options. Disclosures Fajgenbaum: EUSA Pharma: Research Funding; Pfizer: Other: Study drug for clinical trial of sirolimus; N/A: Other: Holds pending provisional patents for 'Methods of treating idiopathic multicentric Castleman disease with JAK1/2 inhibition' and 'Discovery and validation of a novel subgroup and therapeutic target in idiopathic multicentric Castleman disease'.

Circulating proteins to predict adverse COVID-19 outcomes

Predicting COVID-19 severity is difficult, and the biological pathways involved are not fully understood. To approach this problem, we measured 4,701 circulating human protein abundances in two independent cohorts totaling 986 individuals. We then trained prediction models including protein abundances and clinical risk factors to predict adverse COVID-19 outcomes in 417 subjects and tested these models in a separate cohort of 569 individuals. For severe COVID-19, a baseline model including age and sex provided an area under the receiver operator curve (AUC) of 65% in the test cohort. Selecting 92 proteins from the 4,701 unique protein abundances improved the AUC to 88% in the training cohort, which remained relatively stable in the testing cohort at 86%, suggesting good generalizability. Proteins selected from different adverse COVID-19 outcomes were enriched for cytokine and cytokine receptors, but more than half of the enriched pathways were not immune-related. Taken together, these findings suggest that circulating proteins measured at early stages of disease progression are reasonably accurate predictors of adverse COVID-19 outcomes. Further research is needed to understand how to incorporate protein measurement into clinical care.

Human islet T cells are highly reactive to preproinsulin in type 1 diabetes

Cytotoxic CD8 T lymphocytes play a central role in the tissue destruction of many autoimmune disorders. In type 1 diabetes (T1D), insulin and its precursor preproinsulin are major self-antigens targeted by T cells. We comprehensively examined preproinsulin specificity of CD8 T cells obtained from pancreatic islets of organ donors with and without T1D and identified epitopes throughout the entire preproinsulin protein and defective ribosomal products derived from preproinsulin messenger RNA. The frequency of preproinsulin-reactive T cells was significantly higher in T1D donors than nondiabetic donors and also differed by individual T1D donor, ranging from 3 to over 40%, with higher frequencies in T1D organ donors with HLA-A*02:01. Only T cells reactive to preproinsulin-related peptides isolated from T1D donors demonstrated potent autoreactivity. Reactivity to similar regions of preproinsulin was also observed in peripheral blood of a separate cohort of new-onset T1D patients. These findings have important implications for designing antigen-specific immunotherapies and identifying individuals that may benefit from such interventions.

Biomarkers of Coagulation and Inflammation in COVID-19–Associated Ischemic Stroke

Background and Purpose: We sought to determine if biomarkers of inflammation and coagulation can help define coronavirus disease 2019 (COVID-19)–associated ischemic stroke as a novel acute ischemic stroke (AIS) subtype. Methods: We performed a machine learning cluster analysis of common biomarkers in patients admitted with severe acute respiratory syndrome coronavirus 2 to determine if any were associated with AIS. Findings were validated using aggregate data from 3 large healthcare systems. Results: Clustering grouped 2908 unique patient encounters into 4 unique biomarker phenotypes based on levels of c-reactive protein, D-dimer, lactate dehydrogenase, white blood cell count, and partial thromboplastin time. The most severe cluster phenotype had the highest prevalence of AIS (3.6%, P <0.001), in-hospital AIS (53%, P <0.002), severe AIS (31%, P =0.004), and cryptogenic AIS (73%, P <0.001). D-dimer was the only biomarker independently associated with prevalent AIS with quartile 4 having an 8-fold higher risk of AIS compared to quartile 1 ( P =0.005), a finding that was further corroborated in a separate cohort of 157 patients hospitalized with COVID-19 and AIS. Conclusions: COVID-19–associated ischemic stroke may be related to COVID-19 illness severity and associated coagulopathy as defined by increasing D-dimer burden.

Improving workflow in prostate MRI: AI-based decision-making on biparametric or multiparametric MRI

Objectives To develop and validate an artificial intelligence algorithm to decide on the necessity of dynamic contrast-enhanced sequences (DCE) in prostate MRI. Methods This study was approved by the institutional review board and requirement for study-specific informed consent was waived. A convolutional neural network (CNN) was developed on 300 prostate MRI examinations. Consensus of two expert readers on the necessity of DCE acted as reference standard. The CNN was validated in a separate cohort of 100 prostate MRI examinations from the same vendor and 31 examinations from a different vendor. Sensitivity/specificity were calculated using ROC curve analysis and results were compared to decisions made by a radiology technician. Results The CNN reached a sensitivity of 94.4% and specificity of 68.8% (AUC: 0.88) for the necessity of DCE, correctly assigning 44%/34% of patients to a biparametric/multiparametric protocol. In 2% of all patients, the CNN incorrectly decided on omitting DCE. With a technician reaching a sensitivity of 63.9% and specificity of 89.1%, the use of the CNN would allow for an increase in sensitivity of 30.5%. The CNN achieved an AUC of 0.73 in a set of examinations from a different vendor. Conclusions The CNN would have correctly assigned 78% of patients to a biparametric or multiparametric protocol, with only 2% of all patients requiring re-examination to add DCE sequences. Integrating this CNN in clinical routine could render the requirement for on-table monitoring obsolete by performing contrast-enhanced MRI only when needed.

Literacy and Locality in Two Midlands Industrialising Places, 1754-1812

In their extensive research into early modern literacy rates, through the marriage partners' signatures, Roger Schofield and David Cressy alerted us to the potential variability of literacy by region and locality. Modern theorists of literacy have also denoted the desirability of more localised considerations. In an attempt to address that issue in combination with the development of modern society through industrialisation, this article investigates the ability to sign marriage registers (after 1754) as a nominal marker of literacy in two contiguous parishes in north-west Leicestershire, both going through the industrialisation process, but one with more diversity than the monoindustrial character of the other: Loughborough and Shepshed. In addition, the analysis takes into consideration the ability to sign by witnesses to the marriage, as a separate cohort. The printed marriage registers introduced by the Marriage Act of 1753 (26 Geo. II, c. 33), which required signature or mark by two credible witnesses, coincided with the acceleration of industrialisation and thus have particular significance for some localities. In industrialising societies, the decision to attain literacy was also influenced by local social attitudes, such as whether illiteracy carried a social stigma or not.

Limitations of a Commercial Assay as Diagnostic Test of Autoimmune Encephalitis

Detection of neuronal surface antibodies (NSAb) is important for the diagnosis of autoimmune encephalitis (AE). Although most clinical laboratories use a commercial diagnostic kit (Euroimmun, Lübeck, Germany) based on indirect immunofluorescence on transfected cells (IIFA), clinical experience suggests diagnostic limitations. Here, we assessed the performance of the commercial IIFA in serum and CSF samples of patients with suspected AE previously examined by rat brain immunohistochemistry (Cohort A). Of 6213 samples, 404 (6.5%) showed brain immunostaining suggestive of NSAb: 163 (40%) were positive by commercial IIFA and 241 (60%) were negative. When these 241 samples were re-assessed with in-house IIFA, 42 (18%) were positive: 21 (9%) had NSAb against antigens not included in the commercial IIFA and the other 21 (9%) had NSAb against antigens included in the commercial kit (false negative results). False negative results occurred more frequently with CSF (29% vs 10% in serum) and predominantly affected GABABR (39%), LGI1 (17%) and AMPAR (11%) antibodies. Results were reproduced in a separate cohort (B) of 54 AE patients with LGI1, GABABR or AMPAR antibodies in CSF which were missed in 30% by commercial IIFA. Patients with discordant GABABR antibody results (positive in-house but negative commercial IIFA) were less likely to develop full-blown clinical syndrome; no significant clinical differences were noted for the other antibodies. Overall, NSAb testing by commercial IIFA led to false negative results in a substantial number of patients, mainly those affected by anti-LG1, GABABR or AMPAR encephalitis. If these disorders are suspected and commercial IIFA is negative, more comprehensive antibody studies are recommended.

Hyocholic acid species as novel biomarkers for metabolic disorders

Hyocholic acid (HCA) is a major bile acid (BA) species in the BA pool of pigs, a species known for its exceptional resistance to spontaneous development of diabetic phenotypes. HCA and its derivatives are also present in human blood and urine. We investigate whether human HCA profiles can predict the development of metabolic disorders. We find in the first cohort (n = 1107) that both obesity and diabetes are associated with lower serum concentrations of HCA species. A separate cohort study (n = 91) validates this finding and further reveals that individuals with pre-diabetes are associated with lower levels of HCA species in feces. Serum HCA levels increase in the patients after gastric bypass surgery (n = 38) and can predict the remission of diabetes two years after surgery. The results are replicated in two independent, prospective cohorts (n = 132 and n = 207), where serum HCA species are found to be strong predictors for metabolic disorders in 5 and 10 years, respectively. These findings underscore the association of HCA species with diabetes, and demonstrate the feasibility of using HCA profiles to assess the future risk of developing metabolic abnormalities.

Abstract P438: A Reassessment of Hemoglobin and Hematoma Expansion in Intracerebral Hemorrhage

Background: Prior studies identified an increased risk of hematoma expansion (HE) in patients with spontaneous intracerebral hemorrhage (ICH) and lower admission hemoglobin (Hgb) levels. We aimed to externally validate these findings in a separate cohort of ICH patients. Methods: We performed an observational cohort study on consecutive patients with ICH admitted to a Comprehensive Stroke Center over 2 years, using data from an institutional ICH registry. We excluded patients with secondary, non-spontaneous ICH etiologies, as well as patients who arrived >24 hours from symptom onset. Data on HE (defined as an increase of >33% or >6 mL) and 3-month outcomes were prospectively collected, while admission laboratory values were retrospectively abstracted. We compared admission Hgb, INR, and platelet count (Plt) between patients with and without HE, then determined associations between Hgb, HE, and unfavorable 3-month outcomes (modified Rankin Scale 4-6) after adjusting for established ICH predictors, any anticoagulant use, and laboratory markers of coagulopathy with multivariable logistic regression analysis. Results: Of 375 patients, mean age was 73.6 [SD 13.5], 50% (n=187) were male, 85% (n=317) were white, and 19% (n=71) had HE. Admission Hgb values were similar in patients with and without HE (mean [SD] 13.1 [1.8] g/dl vs. 13.1 [1.9] g/dl, p=0.98), as were INR values (median [IQR] 1.1 [1-1.3] vs. 1.1 [1.0-1.2], p=0.15), although patients with HE had modestly lower Plt (median [IQR] 181 [155-230] x 10 9 /l vs. 207 [170-253] x 10 9 /l, p=0.02). In our multivariable models, Hgb was not associated with HE (OR 0.97, 95% CI 0.83-1.12), but odds of unfavorable 3-month outcome increased with lower Hgb levels (OR 0.81 per 1 g/dL Hgb, 95% CI 0.68-0.96). Conclusion: Our study did not confirm prior associations between Hgb and HE, suggesting that if Hgb is implicated in HE, its effects are likely modest. However, Hgb may mediate outcomes in ICH patients via alternative mechanisms.