IMPORTANCE: Myelin oligodendrocyte glycoprotein-IgG1–associated disorder (MOGAD) is a distinct central nervous system–demyelinating disease. Positive results on MOG-IgG1 testing by live cell-based ...assays can confirm a MOGAD diagnosis, but false-positive results may occur. OBJECTIVE: To determine the positive predictive value (PPV) of MOG-IgG1 testing in a tertiary referral center. DESIGN, SETTING, AND PARTICIPANTS: This diagnostic study was conducted over 2 years, from January 1, 2018, through December 31, 2019. Patients in the Mayo Clinic who were consecutively tested for MOG-IgG1 by live cell-based flow cytometry during their diagnostic workup were included. Patients without research authorization were excluded. MAIN OUTCOMES AND MEASURES: Medical records of patients who were tested were initially reviewed by 2 investigators blinded to MOG-IgG1 serostatus, and pretest probability was classified as high or low (suggestive of MOGAD or not). Testing of MOG-IgG1 used a live-cell fluorescence-activated cell-sorting assay; an IgG binding index value of 2.5 or more with an end titer of 1:20 or more was considered positive. Cases positive for MOG-IgG1 were independently designated by 2 neurologists as true-positive or false-positive results at last follow-up, based on current international recommendations on diagnosis or identification of alternative diagnoses; consensus was reached for cases in which disagreement existed. RESULTS: A total of 1617 patients were tested, and 357 were excluded. Among 1260 included patients tested over 2 years, the median (range) age at testing was 46 (0-98) years, and 792 patients were female (62.9%). A total of 92 of 1260 (7.3%) were positive for MOG-IgG1. Twenty-six results (28%) were designated as false positive by the 2 raters, with an overall agreement on 91 of 92 cases (99%) for true and false positivity. Alternative diagnoses included multiple sclerosis (n = 11), infarction (n = 3), B12 deficiency (n = 2), neoplasia (n = 2), genetically confirmed adrenomyeloneuropathy (n = 1), and other conditions (n = 7). The overall PPV (number of true-positive results/total positive results) was 72% (95% CI, 62%-80%) and titer dependent (PPVs: 1:1000, 100%; 1:100, 82%; 1:20-40, 51%). The median titer was higher with true-positive results (1:100 range, 1:20-1:10000) than false-positive results (1:40 range, 1:20-1:100; P < .001). The PPV was higher for children (94% 95% CI, 72%-99%) vs adults (67% 95% CI, 56%-77%) and patients with high pretest probability (85% 95% CI, 76%-92%) vs low pretest probability (12% 95% CI, 3%-34%). The specificity of MOG-IgG1 testing was 97.8%. CONCLUSIONS AND RELEVANCE: This study confirms MOG-IgG1 as a highly specific biomarker for MOGAD, but when using a cutoff of 1:20, it has a low PPV of 72%. Caution is advised in the interpretation of low titers among patients with atypical phenotypes, because ordering MOG-IgG1 in low pretest probability situations will increase the proportion of false-positive results.
Objective
The objective of this study is to determine the association of proliferation indices and pathologic biomarkers on overall and recurrence/metastasis‐free survival (OS and RMFS) in patients ...with sinonasal mucosal melanoma (SNMM) and to assess the genetic mutational landscape of SNMM.
Methods
This is a retrospective cohort study of 45 SNMM patients without neoadjuvant therapy who underwent surgical therapy with curative intent and had tumor tissue available for histopathologic review, molecular analysis, and genetic mutational assessment. The OS and RMFS were assessed for associations with numerous tumor and patient‐related factors.
Results
Among proliferative indices, higher Ki67 and mitotic rates were associated with worsened OS and RMFS (Ki67: p = 0.0007 and p < 0.0001; mitotic rate: p = 0.005 and p = 0.0009, respectively). The presence of brisk tumor‐infiltrating lymphocytes (TILs) was associated with improved RMFS (p = 0.007) and the presence of lymphovascular invasion was associated with worsened OS and RMFS (p = 0.02 and p = 0.04, respectively). Patients with amelanotic tumors were more likely to have higher T‐stage (p = 0.046), less likely to have brisk TILs (p = 0.02) and had worsened RMFS (p = 0.03). Patients on immunotherapy with tumor Ki67 < 40% had better 3‐year OS compared to those with higher Ki67 index (p = 0.004). Actionable genetic mutations such as BRAF V600E are rare and present in only 1 of 20 patients tested.
Conclusion
In SNMM patients, pathologic and proliferation markers such as Ki67, mitotic rate and brisk TILs are associated with survival and may be considered in future staging systems. Clinical response to immunotherapy appears to correlate with the Ki67 index. Given the distinct genetic profile of SNMM, targeted therapies against the MAPK kinase pathway have limited utility.
Level of Evidence
3 Laryngoscope, 132:2350–2358, 2022
Sinonasal mucosal melanoma patients with higher Ki67 indices and higher mitotic rate had worsened overall and recurrence/metastasis‐free survival (OS and RMFS). However, those with brisk tumor infiltrating lymphocytes have improved RMFS. Patients on immunotherapy who had Ki67<40% had better 3‐year OS compared to those with higher Ki67 index.
MYC, a proto-oncogene located on chromosome 8q24, is involved in the control of cell proliferation and differentiation. Previous studies have documented high-level MYC gene amplification and MYC ...overexpression by immunohistochemistry (IHC) in post-irradiation angiosarcomas, but not in primary cutaneous angiosarcoma (AS-C) or in other radiation-associated vascular proliferations, such as atypical vascular lesions. Prompted by our recent finding of MYC amplification in a primary hepatic AS, we analyzed a large number of well-characterized AS-C for MYC amplification and protein overexpression. Formalin-fixed, paraffin-embedded blocks from 38 AS-C were retrieved from our archives and were examined by IHC analysis and fluorescence in-situ hybridization (FISH), using a commercially available antibody and probe. For FISH analysis, the number of copies of MYC was compared with the control gene, CEN8 (MYC/CEN8 ratio). All cases occurred on sun-exposed skin; no patient was known to have a history of therapeutic irradiation. Possible associations between survival and a wide variety of clinicopathological variables were evaluated using the log-rank test. By IHC analysis, MYC overexpression was present in 9/38 (24%) AS-C (2–3+: 6 cases, 16%; 1+: 3 cases, 8%). By FISH analysis, 2/5 (40%) informative cases with 2–3+ immunostaining showed high-level gene amplification. One additional case with 3+ immunostaining showed higher level aneusomy of chromosome 8 (5–8 MYC and CEN8). Two out of fourteen (14%) IHC-negative cases also carried MYC amplification (one high level and one lower level). Low copy number gain of chromosome 8 (3–5 MYC and CEN8) was observed in AS-C with or without MYC expression. MYC amplification and MYC protein overexpression were not correlated with clinical outcome. We have shown, for the first time, MYC gene amplification and protein overexpression in primary (non-radiation-associated) AS of the skin. MYC protein overexpression in cases lacking gene amplification likely reflects other mechanisms of MYC activation. The study of a larger number of AS-C showing MYC amplification may be necessary to determine whether the behavior of such cases differs from their more common non-amplified counterparts.
Type 1 diabetes autoantibodies are directed against multiple antigens including: glutamic acid decarboxylase, protein tyrosine phosphatase-like islet antigen 2 (IA2), insulin (IAA), and Zinc ...transporter 8 protein (ZnT8). The aim of our study was to determine if the presence or titer of ZnT8 antibodies (Ab) was predictive for clinical presentation at diagnosis or for the subsequent disease course.
Between January, 2003 and May, 2019, 105 patients aged ≤21 years with a clinical diagnosis of type 1 diabetes mellitus had at least 1 autoantibody measured. A retrospective chart review was completed. At diagnosis, we evaluated the body mass index z-score, hemoglobin (HbA1c), and the presence of diabetic ketoacidosis (DKA). Complications analyzed post-diagnosis included episodes of DKA, the diagnosis of autoimmune disease, and the presence of vascular complications. We evaluated cumulative lifetime excess glucose as HbA1c area under the curve (AUC) >6%.
Seventy-one patients were ZnT8-Ab(+) (68%), with 19 having low titer ZnT8-Ab and 52 with high titer ZnT8-Ab. Follow-up ranged from 10 days to 15.7 years (median 2.08 years). There were no differences in the characteristics at disease onset or in the subsequent follow-up between those with and those without ZnT8-Ab or those with high or low titers of ZnT8 Ab, except for a small but statistically significant difference in cumulative excess glucose (HbA1c AUC >6%) between those with low and high titers (p=0.0095).
Our study adds to the limited literature on the effect of the presence and titer of ZnT8-Ab in pediatric diabetes. The small effect of ZnT8-Ab titer on glucose excess as measured by HbA1c AUC warrants further study.
Angiosarcoma (AS) is the most common cardiac sarcoma with differentiation, and is poorly characterized from a molecular genetic standpoint. Prognosis remains poor, owing to several factors including ...aggressive tumor biology, poor response to adjuvant therapy, and lack of targeted therapy. The clinical, pathologic and molecular cytogenetic features were studied in ten cardiac AS surgically resected at Mayo Clinic (1994–2015) using a whole genome single nucleotide polymorphism based platform (OncoScan). Mean patient age was 47.8 years, male:female ratio was 1:1.5, and overall median survival was 5.2 months. The most common location was the right atrium (n = 7), with one case each occurring in the epicardium, pericardium, and right ventricle. No patients had received thoracic irradiation. The most common morphology was spindle cell (n = 8), with one case each of epithelioid and biphasic. ERG was the most sensitive vascular marker, with diffuse immunoreactivity in all cases. Several recurrent (present in at least 3 cases) aberrations were identified including trisomies in chromosomes 4, 8, 11, 17, 20, as well as 1q+, and homozygous deletion of CDKN2. Patients who received adjuvant therapy had longer overall survival than those who did not (median 13.4 vs 3.2 months; P = .0283). There were no significant associations between tumor location, histology, immunohistochemical findings, cytogenetic profile, and clinical outcome, however there was a trend towards improved overall survival in patients with tumors harboring 1q + (median 31.8 vs 3.7 months, P = .06). This study confirms recurrent cytogenetic aberrations in cardiac AS, some of which may have prognostic or predictive implications.
Typically, food-related risk assessments are carried out within a four step, technical framework, as detailed by the Codex Alimentarius Commission (World Health Organization/ Food and Agricultural ...Organization of the United Nations, 2015). However, the technical framework presumes a level of ‘objective risk’ and does not take into account that risk is complex and psychologically constructed, something which is rarely acknowledged within risk analysis as a whole. It is well documented that people's perceptions of risk are based on more than merely probability of occurrence, but reflect other non-technical psychological factors (e.g., risk origin, severity, controllability, familiarity). Moreover, the basis of these risk perceptions is largely similar for experts and non-experts.
In this review, we consider each stage of the risk assessment process from a psychological perspective, reviewing research on non-technical factors which could affect assessments of risk and subsequent risk management decisions, with a particular focus on food safety.
We identify 12 factors from the psychological literature which could potentially influence how risks are assessed and characterised. Drawing on insights from this research, we propose a number of recommendations to standardise approaches in risk assessment. Acknowledging and working with the subjectivity of risk is key to ensuring the efficacy of the wider risk analysis process.
•Food risk assessments do not take into account the psychological construction of risk.•Risk perceptions are based on psychological factors other than just probability of occurrence.•The basis of risk perceptions is largely similar for experts and non-experts.•12 factors which could potentially influence how risks are assessed and subsequently managed are identified.•Several recommendations to standardise approaches in risk assessment are proposed.•Risk analysis must acknowledge and work with the subjectivity of risk to ensure its efficacy.
OBJECTIVE:To 1) determine, using contemporary recombinant antigen–based assays, the aquaporin-4 (AQP4)–immunoglobulin G (IgG) detection rate in sequential sera of patients assigned a clinical ...diagnosis of neuromyelitis optica (NMO) but initially scored negative by tissue-based indirect immunofluorescence (IIF) assay; and 2) evaluate the impact of serostatus on phenotype and outcome.
METHODS:From Mayo Clinic records (2005–2011), we identified 163 patients with NMO; 110 (67%) were seropositive by IIF and 53 (33%) were scored seronegative. Available stored sera from 49 “seronegative” patients were tested by ELISA, AQP4-transfected cell-based assay, and in-house fluorescence-activated cell sorting assay. Clinical characteristics were compared based on final serostatus.
RESULTS:Thirty of the 49 IIF-negative patients (61%) were reclassified as seropositive, yielding an overall AQP4-IgG seropositivity rate of 88% (i.e., 12% seronegative). The fluorescence-activated cell sorting assay improved the detection rate to 87%, cell-based assay to 84%, and ELISA to 79%. The sex ratio (female to male) was 1:1 for seronegatives and 9:1 for seropositives (p < 0.0001). Simultaneous optic neuritis and transverse myelitis as onset attack type (i.e., within 30 days of each other) occurred in 32% of seronegatives and in 3.6% of seropositives (p < 0.0001). Relapse rate, disability outcome, and other clinical characteristics did not differ significantly.
CONCLUSIONS:Serological tests using recombinant AQP4 antigen are significantly more sensitive than tissue-based IIF for detecting AQP4-IgG. Testing should precede immunotherapy; if negative, later-drawn specimens should be tested. AQP4-IgG–seronegative NMO is less frequent than previously reported and is clinically similar to AQP4-IgG–seropositive NMO.
Abstract
The Mermin-Wagner theorem states that long-range magnetic order does not exist in one- (1D) or two-dimensional (2D) isotropic magnets with short-ranged interactions. Here we show that in ...finite-size 2D van der Waals magnets typically found in lab setups (within millimetres), short-range interactions can be large enough to allow the stabilisation of magnetic order at finite temperatures without any magnetic anisotropy. We demonstrate that magnetic ordering can be created in 2D flakes independent of the lattice symmetry due to the intrinsic nature of the spin exchange interactions and finite-size effects. Surprisingly we find that the crossover temperature, where the intrinsic magnetisation changes from superparamagnetic to a completely disordered paramagnetic regime, is weakly dependent on the system length, requiring giant sizes (
e.g
., of the order of the observable universe ~ 10
26
m) to observe the vanishing of the magnetic order as expected from the Mermin-Wagner theorem. Our findings indicate exchange interactions as the main ingredient for 2D magnetism.
To compare the rate of lost reduction between 2 groups of non-age-segregated type III supracondylar humeral fracture patients: a unicolumnar versus bicolumnar fixation group.
Retrospective cohort ...study.
Pediatric Academic Trauma Center.
We identified 257 patients with type III supracondylar humerus fractures from surgical billing records over a 5-year period. There were 183 patients identified with bicolumnar fixation (71.2%) and 74 patients identified with unicolumnar fixation (28.8%).
Closed reduction percutaneous pinning of the distal humerus.
The primary outcome measure was difference in rate of lost reduction between patients with bicolumnar (lateral and medial column) and unicolumnar (lateral column only) fixation (Fig. 1). The reduction and fixation at the time of fluoroscopy was assessed using the Baumann angle, Gordon index, and anterior humeral line. Loss of reduction was assessed at time of healing, defined by a Baumann angle change ≥10 degrees and Gordon index of ≥50% (Fig. 2).
There were 183 patients with bicolumnar fixation and 74 patients with unicolumnar fixation included in the study (average age 5.8 years; range, 2-14 years). The rate of lost reduction in patients with bicolumnar fixation was 6.01% (11/183), whereas 17.57% (13/74) of patients with unicolumnar fixation experienced lost reduction. These rates were significantly different (P = 0.008) with a 3.3 times higher odds (95% confidence interval = 1.3-8.6) of lost reduction with unicolumnar fixation.
There is a statistically significant increase in the rate of supracondylar fracture loss of reduction for patients with unicolumnar fixation when compared with bicolumnar fixation.
Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.
Zoonoses represent a global public health threat. Understanding lay perceptions of risk associated with these diseases can better inform proportionate policy interventions that mitigate their current ...and future impacts. While individual zoonoses (e.g. bovine spongiform encephalopathy) have received scientific and public attention, we know little about how multiple zoonotic diseases vary relative to each other in lay risk perceptions. To this end, we examined public perceptions of 11 zoonoses across 12 qualitative attributes of risk among the UK public (
n
= 727, volunteer sample), using an online survey. We found that attribute ratings were predominantly explained via two basic dimensions of risk related to public knowledge and dread. We also show that, despite participants reporting low familiarity with most of the diseases presented, zoonoses were perceived as essentially avoidable. These findings imply that infection is viewed as dependent upon actions under personal control which has significant implications for policy development.
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