The biophysical and compositional properties of human basement membranes.

Basement membranes are among the most widespread, non-cellular functional materials in metazoan organisms. Despite this ubiquity, the links between their compositional and biophysical properties are often difficult to establish due to their thin and delicate nature. In this article, we examine these features on a molecular level by combining results from proteomics, elastic, and nanomechanical analyses across a selection of human basement membranes. Comparing results between these different membranes connects certain compositional attributes to distinct nanomechanical signatures and further demonstrates to what extent water defines these properties. In all, these data underline BMs as stiff yet highly elastic connective tissue layers and highlight how the interplay between composition, mechanics and hydration yields such exceptionally adaptable materials.

Secondary Primary Cancer Risk After Radiation Therapy in Rectal Cancer: A Population-Based Cohort Study With Propensity Score Matching.

BACKGROUND: It remains unclear whether radiation therapy (RT) has an impact on the development of secondary primary cancer (SC) in rectal cancer (RC) patients, especially within the true pelvis. AIM: To examine the incidence of SC in a population-based cohort of RC after surgical treatment with or without radiation therapy (RT, NRT). PATIENTS AND METHODS: The epidemiological cohort consisting of 13,919 RC patients with primary M0 stage diagnosed between 1998 and 2019 was collected from cancer registry data of Upper Bavaria. Competing risk analyses were conducted regarding the development of SC on 11 687 first malignancies, stratified by RT/NRT. A propensity score (PS) was generated by logistic regression modeling of RT to repeat competing risk analyses on a PS-matched cohort. RESULTS: The median age (interquartile range) of the epidemiological cohort was 68.9 years (60.4-76.7). About 60.8%, were men, 38.7% had UICC III, 35.8% of tumors were localized lower than 8 cm, 41.3% underwent RT. Only 17.1% of patients older than 80 years at diagnosis received RT. In general, RT patients were 5 years younger than NRT patients (65.9 years [58.0-73.0] vs. 71.3 years [62.4-79.2], P < .0001). The 20-year cumulative incidence of SC was 16.5% in RT and 17.4% in NRT patients (P = .2298). Men with RT had a lower risk of prostate cancer (HR = 0.55, 95%CI [0.34-0.91], P = .0168). In the PS-matched cohort, RT patients had a significantly higher risk of bladder cancer during follow-up (10-year cumulative incidence of 1.1% vs. 0.6% in NRT). The direction of the RT effects in men and women and different tumor sites may cancel each other. CONCLUSION: A protective effect of RT in rectal cancer patients on developing prostate SC by half is reproduced. Further analyses studying the long-term SC risks of RT should essentially focus on stratification by sex, and focus on more recent data.

Expanding mammography screening for women aged 40-80 years: evidence from a modeling approach using real-world data.

If a mammography screening program (MS) is to be expanded, the benefit must be demonstrated for each additional age cohort. For the age interval between 40 and 80 years, the association between tumor-related and tumor-independent mortality of 21 2-year cohorts is modeled using up-to-date, valid data to determine MS outcome. Disease trajectories with and without biennial MS are extrapolated for each age cohort using the available data and knowledge on MS. The competing mortality is randomly generated for each age cohort with and without MS for a follow-up period of 20 years. Analyses of the modeled cohorts describe incremental change for each year, quantifying the changing benefits of MS. With increasing age, the proportion of tumor-independent mortality before and with metastatic disease increases and the benefit decreases. The simulations with 21 studies on the age interval 40-80 years provide four parameters to determine the benefits and costs of MS: The number of prevented deaths, required mammography screening exams (MSE) and their costs, life-years gained, and the required MSEs. If one additional MSE is offered for age groups 48/70 years, this will result in 311/320 prevented breast cancer (BC) deaths with 1742/1494 required MSEs or 8784/4168 life-years gained with 64/140 required MSEs. A rational cutoff cannot be quantified. The mortality effect of MS between 40 and 80 years is quantified in 21 steps using two metrics, number of MSEs per tumor-related mortality prevented and per life-year gained. This provides a decision support for stepwise expansions. Given this real-world evidence no rational age cutoffs for MS becomes evident. A society has to decide which MS costs, including side effects of MS for women who remain BC-free, it is willing and able to accept in order to reduce breast cancer mortality.

Validation of the German Version of the P4 Suicidality Tool.

For general practitioners (GPs), it may be challenging to assess suicidal ideation (SI) in patients. Although promising instruments exist for the use in primary care, only a few have been validated in German. The objectives of this study were to examine the validity of the brief P4 screener for assessing SI in a cross-sectional study including outpatients. Inclusion criteria were a PHQ-9 score ≥ 10 or an affirmative answer to its SI item. Construct validity of the P4 was examined by comparison with the four-item Suicide Behaviors Questionnaire-Revised (SBQ-R), the PHQ-9 (convergent), and the positive mental health (PMH) scale (divergent). The study sample included 223 patients (mean age 47.61 ± 15 years; 61.9% women) from 20 primary care practices (104 patients) and 10 psychiatric/psychotherapeutic clinics (119 patients). The first three items of the P4 correlate positively with most of the four items of the reference standard SBQ-R (convergent validity); the fourth item of the P4 (preventive factors) correlates significantly with the PMH scale. The most common preventive factor (67%) is family or friends. The German P4 screener can be used to assess SI in outpatient care. It explores preventive or protective factors of suicide, which may support the GP's decision on treatment. We recommend a further clinical interview for patients flagged by P4 assessment in order to more formally assess suicidal risk.

[Thyroid Eye Disease-Compressive Optic Neuropathy]. / Optikuskompression bei endokriner Orbitopathie.

BACKGROUND: The aim of this study was to evaluate the functional outcomes in terms of best-corrected visual acuity (BCVA) and visual field (VF) defects in optic nerve compression (thyroid eye disease-compressive optic neuropathy, TED-CON) patients after treatment. PATIENTS AND METHODS: In this observational, retrospective study, the medical charts of 51 patients (96 eyes) with a diagnosis of definitive TED-CON between 2010-2020 were included. RESULTS: After the diagnosis of TED-CON, 16 patients (27 eyes) received steroid-pulse (medical) treatment alone, 67 eyes received an additional surgical orbital decompression, whereas 1 patient (2 eyes) refused both treatment methods. In 74 eyes (77.1%) we detected an improvement of the BCVA ≥ 2 lines after the treatment over a mean time interval of 31.7 weeks (with no significant difference between treatment methods). In 22 eyes (27.2%) out of the 81 that underwent a posttreatment VF examination, we observed a complete resolution of the defects over a mean time interval of 39.9 weeks. When we limited analysis to patients with a minimum follow-up of 6 months at last visit, we found 33 eyes (61.1%) out of 54 eyes still had a VF defect. CONCLUSION: In our data, more than half of the TED-CON cases (61.5%) had a good prognosis with a final BCVA ≥ 0.8  at the last visit; however, only 22 eyes (27.2%) showed a complete resolution of VF defects, while 33 eyes (61.1%) had residual defects measured after a minimum follow-up of 6 months. These results suggest that while the BCVA recovers relatively well, the VF of patients is likely to remain marked by optic nerve compression.

The other colon cancer: a population-based cohort study of appendix tumour trends and prognosis.

AIM: Appendiceal neoplasms are rare subtypes of colorectal tumours that mainly affect younger patients some 20 years earlier than other colon tumours. The aim of this study was to gain more insight into the histological subtypes of this rare disease and include cases previously excluded, such as mucinous neoplasia. METHOD: The cohort study included 1097 patients from the Munich Cancer Registry (MCR) diagnosed between 1998 and 2020. Joinpoint analysis was used to determine trend in incidence. Baseline demographic comparisons and survival analyses using competing risk and univariate/multivariate methods were conducted according to tumour histology: adenocarcinoma (ADENO), neuroendocrine neoplasia (NEN), mixed adeno-neuroendocrine carcinoma (MANEC), and low- (LAMN) and high-grade mucinous neoplasia (HAMN). RESULTS: Up to 2016 the number of cases increased significantly [annual per cent change (APC) = 6.86, p < 0.001] followed by a decline in the following years (APC = -14.82, p = 0.014; average APC = 2.5, p = 0.046). Comparison of all patients showed that NEN (48.4%) and mucinous neoplasms (11.6%) had a considerably better prognosis than ADENO (36.0%) and MANEC (3.0%, p < 0.0001). A multivariate analysis within the NEN and ADENO subgroups revealed that further histological classification was not prognostically relevant, while older age and regional tumour spread at diagnosis were associated with a poor prognosis. ADENO histology with high tumour grade and appendectomy only was also associated with poorer survival. CONCLUSION: Appendiceal neoplasms are histologically heterogeneous; however, this diversity becomes less relevant compared with the marked difference from cancers of the remaining colon. The previously observed increase in cases appears to be abating; fewer cases of appendicitis and/or appendectomies or changes in histopathological assessment may be behind this trend.

Breast cancer: emerging principles of metastasis, adjuvant and neoadjuvant treatment from cancer registry data.

PURPOSE: Growing primary breast cancers (PT) can initiate local recurrences (LR), regional lymph nodes (pLN) and distant metastases (MET). Components of these progressions are initiation, frequency, growth duration, and survival. These characteristics describe principles which proposed molecular concepts and hypotheses must align with. METHODS: In a population-based retrospective modeling approach using data from the Munich Cancer Registry key steps and factors associated with metastasis were identified and quantified. Analysis of 66.800 patient datasets over four time periods since 1978, reliable evidence is obtained even in small subgroups. Together with results of clinical trials on prevention and adjuvant treatment (AT) principles for the MET process and AT are derived. RESULTS: The median growth periods for PT/MET/LR/pLN comes to 12.5/8.8/5/3.5 years, respectively. Even if 30% of METs only appear after 10 years, a pre-diagnosis MET initiation principle not a delayed one should be true. The growth times of PTs and METs vary by a factor of 10 or more but their ratio is robust at about 1.4. Principles of AT are 50% PT eradication, the selective and partial eradication of bone and lung METs. This cannot be improved by extending the duration of the previously known ATs. CONCLUSION: A paradigm of ten principles for the MET process and ATs is derived from real world data and clinical trials indicates that there is no rationale for the long-term application of endocrine ATs, risk of PTs by hormone replacement therapies, or cascading initiation of METs. The principles show limits and opportunities for innovation also through alternative interpretations of well-known studies. The outlined MET process should be generalizable to all solid tumors.

Evaluation of visual evoked potentials in dysthyroid optic neuropathy.

PURPOSE: To evaluate the findings of visual evoked potentials (VEP) in patients with dysthyroid optic neuropathy (DON). METHODS: In this observational, cross-sectional study 40 eyes (22 patients) with a diagnosis of DON were included. RESULTS: We discovered that in 16 out of 37 eyes with pattern-VEP (p-VEP), the latency of P100 wave was normal in spite of having a diagnosis of DON. The same pattern was also observed in the measurement of the amplitude of P100 wave: in 28 out of 37 eyes with p-VEP the amplitudes were observed as normal. In 3 eyes of 3 patients p-VEP showed no response, therefore a flash-VEP (f-VEP) was performed. Flash-VEPs of those patients indicated a prolonged P100 latency with a reduced amplitude. The sensitivity of abnormal P100 latency was 56.8% (95%CI 39.5-72.9%); and that of reduced P100 amplitude was 24.3% (95%CI 11.8-41.2%). Also, in 40 eyes color vision test by Arden was performed. In 36 eyes (20 patients) the tritan value was pathological (based on a threshold of ≥8%). CONCLUSION: According our data, VEP seems to have a limited potential especially in patients with a good best-corrected visual acuity (BCVA ≤0.2 LogMAR) for identifying the optic nerve involvement. The fact that P100 latency and amplitude were normal even in cases with an optic nerve swelling makes us question the usefulness of the VEP for diagnosing cases of DON in daily clinical life.

Evaluating the interreader agreement and intrareader reproducibility of Visual Field Defects in Thyroid Eye Disease- Compressive Optic Neuropathy.

PURPOSE: To categorize visual field (VF) defects according to Freitag and Tanking's (FT) classification in Thyroid Eye Disease-Compressive Optic Neuropathy (TED-CON) and evaluate the interreader agreement and intrareader reproducibility of the classification. SUBJECTS AND METHODS: In this retrospective, observational study we included medical reports of 96 eyes (51 patients), who underwent VF testing with TED-CON in Ludwig-Maximilians-University (2008-2019). Two readers separately examined the VFs at the time of the TED-CON diagnosis, each offering two readings of the same VF in a time interval of 1 month. None of our patients were diagnosed with only VF testing. The visual field testing was only performed when the inclusion criteria for TED-CON were met. RESULTS: The most common VF defects upon TED-CON diagnosis were stage 1b defects in FT classification (34.4% for reader 1, 35.4% for reader 2), followed by stage 2b (10.4% for reader 1, 14.6% for reader 2), and stage 3 (10.4% for both readers). The overall interreader agreement between 2 examiners was substantial for the first reading (69.8% agreement, kappa 0.635 (95% CI [0.525-0.745])) and moderate for the second reading (66.7% agreement, kappa 0.598 (95% CI [0.488-0.708])). The intrareader reproducibility ranged from substantial to almost perfect (78.1% agreement) between readings (kappa 0.736 (95%CI [0.638-0.834])) for reader 1 and 90.6% agreement (kappa 0.885 (95%CI [0.814-0.956])) for reader 2. CONCLUSION: We found good BCVA (LogMAR ≤ 0.2), in nearly half of the cases (44 eyes, 45.8%) and also, strikingly near perfect visual acuity (BCVA LogMAR ≤0.1) in 22.9% of the cases (22 eyes) with TED-CON. We conclude that clinicians should be alert to VF defects in the inferior region (stage 1a/1b in the FT classification) even in patients with a good BCVA.

Loss of SATB2 Occurs More Frequently Than CDX2 Loss in Colorectal Carcinoma and Identifies Particularly Aggressive Cancers in High-Risk Subgroups.

BACKGROUND: Special AT-rich sequence-binding protein 2 (SATB2) has emerged as an alternative immunohistochemical marker to CDX2 for colorectal differentiation. However, the distribution and prognostic relevance of SATB2 expression in colorectal carcinoma (CRC) have to be further elucidated. METHODS: SATB2 expression was analysed in 1039 CRCs and correlated with clinicopathological and morphological factors, CDX2 expression as well as survival parameters within the overall cohort and in clinicopathological subgroups. RESULTS: SATB2 loss was a strong prognosticator in univariate analyses of the overall cohort (p < 0.001 for all survival comparisons) and in numerous subcohorts including high-risk scenarios (UICC stage III/high tumour budding). SATB2 retained its prognostic relevance in multivariate analyses of these high-risk scenarios (e.g., UICC stage III: DSS: p = 0.007, HR: 1.95), but not in the overall cohort (DSS: p = 0.1, HR: 1.25). SATB2 loss was more frequent than CDX2 loss (22.2% vs. 10.2%, p < 0.001) and of higher prognostic relevance with only moderate overlap between SATB2/CDX2 expression groups. CONCLUSIONS: SATB2 loss is able to identify especially aggressive CRCs in high-risk subgroups. While SATB2 is the prognostically superior immunohistochemical parameter compared to CDX2 in univariate analyses, it appears to be the less sensitive marker for colorectal differentiation as it is lost more frequently.

[Short screener for suicidal behaviour in primary care - a systematic review]. / Kurze Screener für Suizidalität in der Allgemeinmedizin : Eine systematische Übersichtsarbeit.

BACKGROUND: We summarize the available studies reporting diagnostic accuracy of brief instruments for suicidal behaviour in primary care. METHOD: Databases MEDLINE, EMBASE, PsychINFO, PSYNDEX, and Cochrane Library were searched without any time constraints. Risk of bias and applicability concerns were assessed using the QUADAS-2 tool. The certainty of evidence was rated via GRADEpro. We included studies on primary care patients or participants from the general population. Suicidal behaviour was the defined target condition. With respect to the applicability in a primary care setting we included only studies assessing brief screening instruments; a brief instrument was defined as having no more than 12 items. We assessed sensitivity, specificity, and positive and negative predictive value. RESULTS: A total of 12,460 studies were identified; of those, n = 7 fulfilled all strong criteria and were included. The range of sensitivity was 0.26-1.00, specificity was 0.64-0.99, positive predictive value 0.06-0.91, negative predictive value 0.83-1.00. Risk of bias was rated moderate and concerns regarding applicability acceptable. A required sensitivity of at least 0.80 and specificity of 0.50 with a moderate to high GRADE rating was achieved by 8 of 11 index tests. CONCLUSIONS: Brief screening instruments can support ruling-out suicidality, but are less suitable for ruling-in. They may support general practitioners in an initial assessment, but in case of a positive test result, a valid diagnostic assessment should be done by a structured clinical interview.

Loss of CDX2 in colorectal cancer is associated with histopathologic subtypes and microsatellite instability but is prognostically inferior to hematoxylin-eosin-based morphologic parameters from the WHO classification.

BACKGROUND: Immunohistochemical loss of CDX2 has been proposed as a biomarker of dismal survival in colorectal carcinoma (CRC), especially in UICC Stage II/III. However, it remains unclear, how CDX2 expression is related to central hematoxylin-eosin (HE)-based morphologic parameters defined by 2019 WHO classification and how its prognostic relevance is compared to these parameters. METHODS: We evaluated CDX2 expression in 1003 CRCs and explored its prognostic relevance compared to CRC subtypes, tumour budding and WHO grade in the overall cohort and in specific subgroups. RESULTS: CDX2-low/absent CRCs were enriched in specific morphologic subtypes, right-sided and microsatellite-instable (MSI-H) CRCs (P < 0.001) and showed worse survival characteristics in the overall cohort/UICC Stage II/III (e.g. DFS: P = 0.005) and in microsatellite stable and left-sided CRCs, but not in MSI-H or right-sided CRCs. Compared with CDX2, all HE-based markers showed a significantly better prognostic discrimination in all scenarios. In multivariate analyses including all morphologic parameters, CDX2 was not an independent prognostic factor. CONCLUSION: CDX2 loss has some prognostic impact in univariate analyses, but its prognostic relevance is considerably lower compared to central HE-based morphologic parameters defined by the WHO classification and vanishes in multivariate analyses incorporating these factors.

A pathological indicator for dysthyroid optic neuropathy: tritan color vision deficiency.

PURPOSE: To investigate the sensitivity of the color vision test by Arden in patients with dysthyroid optic neuropathy (DON) to improve diagnosis. METHODS: In this observational, retrospective study, we included the medical records of 92 eyes (48 patients) with diagnosis of DON between 2008 and 2019 in order to evaluate the full spectrum of findings from the color vision test by Arden, and to determine potential importance of this test. Thirty-five patients were female, and 13 patients were male. The mean age was 58.0 years (range: 34-79) at the time of the DON diagnosis. RESULTS: Forty-one eyes displayed relatively good BCVA with ≤ 0.2 LogMAR. We found a protan value exceeding the threshold of ≥ 8% in 57 eyes (30 patients) at the time of the diagnosis. The sensitivity of protan was 61.9% (95% CI 51.2-71.8%), while that of tritan was a striking 98.9% (95% CI 94.1-99.9%). We discovered one pathological sign, tritan deficiency (based on a threshold of ≥ 8%) consistently in all eyes but one at the time of the diagnosis, regardless of the visual field defects or any changes in best-corrected visual acuity (BCVA). CONCLUSION: We found blue-yellow (tritan) deficiency, to be a sensitive and reliable indicator of dysthyroid optic neuropathy. We conclude that, in cases with suspected DON, a color vision test that can detect tritan deficiency is an essential tool for the adequate assessment, diagnosis, and treatment of DON.

Morphology Matters: A Critical Reappraisal of the Clinical Relevance of Morphologic Criteria From the 2019 WHO Classification in a Large Colorectal Cancer Cohort Comprising 1004 Cases.

The 2019 World Health Organization (WHO) classification of colorectal carcinoma (CRC) profoundly reclassified CRC subtypes and introduces tumor budding as a second major grading criterion, while condensing conventional grade into a 2-tiered system. So far it remains largely unexplored how these parameters interact with each other and whether they truly have an independent impact on patient prognosis. We reclassified a large single-center cohort of 1004 CRCs spanning 2 decades for adjusted WHO grade (low vs. high), tumor budding (Bd1/Bd2/Bd3), and CRC subtype (adenocarcinoma not otherwise specified, micropapillary, mucinous, serrated, medullary, adenoma-like, signet-ring cell, mixed adenoneuroendocrine carcinoma/neuroendocrine carcinoma, undifferentiated) according to the criteria of the 2019 WHO classification. We investigated the interaction of these parameters, their connection to stage/microsatellite status, and their significance for patient survival in the different subgroups. Specific subtypes other than adenocarcinoma not otherwise specified represented one third of all CRCs and were unevenly distributed throughout stage and microsatellite subgroups. Subtypes, WHO grade and tumor budding profoundly impacted all survival parameters (P<0.001 for all analyses), with CRC subtypes and tumor budding-but not WHO grade-being stage-independent prognosticators for all survival comparisons. WHO grade had very limited prognostic value in CRC subtypes, while tumor budding retained its strong prognostic impact in most scenarios. Accurate delineation of CRC subtypes introduced in the 2019 WHO classification provides strong stage-independent prognostic information, arguing that they should be considered in pathology reports and in clinical trials. Of the morphology-based grading schemes included in the 2019 WHO, tumor budding outperforms WHO grade.

Colonoscopy and polypectomy: beside age, size of polyps main factor for long-term risk of colorectal cancer in a screening population.

PURPOSE: Despite national and international guideline recommendations, few studies have been conducted to estimate the impact of colonoscopy screening on long-term colorectal cancer incidence. Aim of this study was to determine the long-term impact of a full colonoscopy with polypectomy on colorectal cancer incidence in a large screening population. METHODS: In this prospective observational cohort study, a total of 10,947 colonoscopy screening participants from within the scope of the Munich Cancer Registry were consecutively recruited from participating gastroenterology practices and their subsequent colorectal cancer incidence assessed. Predictive factors associated with colorectal cancer were also evaluated in univariate and multivariate analyses. RESULTS: After a median follow-up of 14.24 years (95% CI [14.21-14.25]), 93 colorectal cancer cases were observed. This is equivalent to a truncated age-standardized rate of 69.0 (95% CI [43.3-94.7]) for male and 43.4 (95% CI [29.4-57.5]) for female participants (≥ 50 years at colonoscopy). The ratio of this observed to the expected rate from cancer registry data showed a 67% decrease in colorectal cancer incidence in the male and 65% in the female participants (p < 0.0001). In multivariate analysis of screening patients, age at screening (p < 0.0001) was the main predictive factor for colorectal cancer. In the subgroup with positive polyp findings, age (p < 0.0001) and the polyp size (p = 0.0002) were associated with colorectal cancer. CONCLUSION: These results underline the significance of a full colonoscopy screening combined with polypectomy in reducing the total disease burden of colorectal cancer.

Oral insulin immunotherapy in children at risk for type 1 diabetes in a randomised controlled trial.

AIMS/HYPOTHESIS: Oral administration of antigen can induce immunological tolerance. Insulin is a key autoantigen in childhood type 1 diabetes. Here, oral insulin was given as antigen-specific immunotherapy before the onset of autoimmunity in children from age 6 months to assess its safety and immune response actions on immunity and the gut microbiome. METHODS: A phase I/II randomised controlled trial was performed in a single clinical study centre in Germany. Participants were 44 islet autoantibody-negative children aged 6 months to 2.99 years who had a first-degree relative with type 1 diabetes and a susceptible HLA DR4-DQ8-containing genotype. Children were randomised 1:1 to daily oral insulin (7.5 mg with dose escalation to 67.5 mg) or placebo for 12 months using a web-based computer system. The primary outcome was immune efficacy pre-specified as induction of antibody or T cell responses to insulin and measured in a central treatment-blinded laboratory. RESULTS: Randomisation was performed in 44 children. One child in the placebo group was withdrawn after the first study visit and data from 22 insulin-treated and 21 placebo-treated children were analysed. Oral insulin was well tolerated with no changes in metabolic variables. Immune responses to insulin were observed in children who received both insulin (54.5%) and placebo (66.7%), and the trial did not demonstrate an effect on its primary outcome (p = 0.54). In exploratory analyses, there was preliminary evidence that the immune response and gut microbiome were modified by the INS genotype Among children with the type 1 diabetes-susceptible INS genotype (n = 22), antibody responses to insulin were more frequent in insulin-treated (72.7%) as compared with placebo-treated children (18.2%; p = 0.03). T cell responses to insulin were modified by treatment-independent inflammatory episodes. CONCLUSIONS/INTERPRETATION: The study demonstrated that oral insulin immunotherapy in young genetically at-risk children was safe, but was not associated with an immune response as predefined in the trial primary outcome. Exploratory analyses suggested that antibody responses to oral insulin may occur in children with a susceptible INS genotype, and that inflammatory episodes may promote the activation of insulin-responsive T cells. TRIAL REGISTRATION: Clinicaltrials.gov NCT02547519 FUNDING: The main funding source was the German Center for Diabetes Research (DZD e.V.).

Subclinical dysthyroid optic neuropathy: tritan deficiency as an early sign of dysthyroid optic neuropathy.

PURPOSE: The aim of this research was to investigate the subclinical findings of dysthyroid optic neuropathy (DON) and to look for early indicators for optic nerve compression in patients with Graves' orbitopathy. PATIENTS AND METHODS: In this observational, retrospective study, the medical charts of 24 patients (32 eyes) with a diagnosis of DON between 2008 and 2019 were included. Our goal was to identify potential pathological signs in patients with DON prior to the definitive diagnosis of DON. RESULTS: We discovered that the earliest pathological sign in the subclinical cases was tritan deficiency obtained with a standardised colour vision test by Arden. In all cases but one, regardless of the visual field (VF) defects, the tritan values were pathological (based on a threshold of ≥8%) in the subclinical phase. The mean tritan value was 19.12% (range 6.9-80.8%) at the time of the subclinical phase and 32.16% (range 6.3-100.0%) at the time of the diagnosis of DON. The sensitivity of the colour vision test was 20% for protan and 96.67% for tritan in the subclinical phase. At the time of the definitive diagnosis of DON, the sensitivity of protan was 48.15% compared to 96.30% for tritan. CONCLUSION: We found that changes in vision affecting the blue-yellow (tritan) colours resulting from the compression of optic nerve, even in affected patients with normal VF tests, are a reliable early sign of DON.