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Background/objectives: Tamoxifen has well-known retinal toxicity, but the epidemiology of this toxicity is poorly defined. This study aims to 1) evaluate the prevalence of tamoxifen retinopathy in a major northeastern metropolitan area based on multimodal retinal imaging and 2) determine whether the additional peripheral retina captured in ultra-widefield (UWF) imaging aids in the diagnosis of tamoxifen retinopathy., Methods: This retrospective cohort study examined female patients initiated on tamoxifen for at least 12 months prior to their first retinal exam. Two independent graders performed blinded review of spectral-domain optical coherence tomography (OCT) images for evidence of macular toxicity and UWF images for signs of central and peripheral toxicity. A one-tailed two-proportion Z-test determined whether peripheral pigmentary changes were more prevalent in the tamoxifen cohort than age- and gender-matched controls., Results: 241 eyes from 123 patients were included in the tamoxifen cohort, and 258 eyes from 132 patients were included in the control cohort. Two patients demonstrated definitive tamoxifen retinopathy, for a prevalence of 1.6%. One patient demonstrated crystalline maculopathy on OCT and UWF imaging, while another demonstrated pseudocystic cavitations on OCT imaging. Neither patient had peripheral findings on UWF imaging. Peripheral pigmentary changes were not significantly more prevalent in the tamoxifen cohort., Conclusions: These findings suggest that UWF imaging does not contribute to diagnosis of tamoxifen retinopathy, and OCT may be the most valuable tool in diagnosing tamoxifen retinopathy. Our prevalence (1.6%) diverges from higher rates in studies screening with similarly advanced retinal imaging. Further large population studies are needed., (Copyright © 2024 Canadian Ophthalmological Society. Published by Elsevier Inc. All rights reserved.)

Introduction: An increasing number of studies have demonstrated that acupuncture can influence Autonomic Nervous System functions. Heart Rate variability (HRV) is one widely used marker of autonomic activity. The main objective of this systematic review is to critically assess the evidence from randomized clinical trials (RCTs) regarding the effect of acupuncture on HRV as compared to placebo methods., Method: EMBASE, Pubmed, The Cochrane Library, Web of Science, Scopus electronic databases were searched until 9 September 2020 for RCTs in which human subjects were treated with needle acupuncture using acupoints of the body without electric stimulation., Results: The searches identified 1698 potentially relevant articles, 9 RCTs were included. The statistical analysis of the available data showed that the changes between pre and post treatment HF (high frequency) and LF/HF (high frequency/low frequency) values in Verum group were significant, while there were no significant changes in these parameters in Sham groups., Conclusion: the results of this meta-analysis suggest that real acupuncture has superior effect over placebo acupuncture in increasing parasympathetic tone and in this way may improve physical well-being. Due to the quality of primary studies and degree of heterogeneity the results should be interpreted cautiously., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Extensive research is focused on the role of liquid biopsy in pancreatic cancer since reliable diagnostic and follow-up biomarkers represent an unmet need for this highly lethal malignancy. We performed a systematic review and meta-analysis on the prognostic value of exosomal biomarkers in pancreatic ductal adenocarcinoma (PDAC). MEDLINE, Embase, Scopus, Web of Science, and CENTRAL were systematically searched on the 18th of January, 2021 for studies reporting on the differences in overall (OS) and progression-free survival (PFS) in PDAC patients with positive vs negative exosomal biomarkers isolated from blood. The random-effects model estimated pooled multivariate-adjusted (AHR) and univariate hazard ratios (UHRs) with 95% confidence intervals (CIs). Eleven studies comprising 634 patients were eligible for meta-analysis. Detection of positive exosomal biomarkers indicated increased risk of mortality (UHR = 2.81, CI:1.31-6,00, I 2  = 88.7%, P < 0.001), and progression (UHR = 3.33, CI: 2.33-4.77, I 2  = 0, P = 0.879) across various disease stages. Positive exosomal biomarkers identified preoperatively revealed a higher risk of mortality in resectable stages (UHR = 5.55, CI: 3.24-9.49, I 2  = 0, P = 0.898). The risk of mortality in unresectable stages was not significantly increased with positive exosomal biomarkers (UHR = 2.51, CI: 0.55-11.43, I 2  = 90.3%, P < 0.001). Detectable exosomal micro ribonucleic acids were associated with a decreased OS (UHR = 4.08, CI: 2.16-7.69, I 2  = 46.9%, P = 0.152) across various stages. Our results reflect the potential of exosomal biomarkers for prognosis evaluation in PDAC. The associated heterogeneity reflects the variability of study methods and need for their uniformization before transition to clinical use., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Despite routine supplementation, vitamin D insufficiency is often seen in cystic fibrosis (CF) patients on account of pancreatic insufficiency. Vitamin D is a crucial component of bone health and affects nearly all cells of the immune system. However, clinical benefits or harms associated with supplementation are poorly documented. In this systematic review, we included randomized controlled trials (RCTs) that compared vitamin D supplementation with placebo (i.e. 'non-increased dose') in CF patients. Analysing the 8 included RCTs, the intervention group had significantly higher serum 25-hydroxyvitamin D (se25OHD) levels, but there were no significant differences found in the quantitative synthesis of clinical outcomes, including bone disease-, respiratory status- and immunological status-related outcomes. Based on our current results, while a higher vitamin D dose elevates se25OHD, it does not seem to influence clinical outcomes. Future RCTs should include outcomes of past studies and apply longer follow-up periods to document long-term patient-important outcomes., Competing Interests: Declaration of Competing Interest Authors disclose no conflicts of interest., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: To assess anti-vascular endothelial growth factor (VEGF) management patterns and anatomic and visual acuity (VA) outcomes among patients with neovascular age-related macular degeneration (nAMD) in United States clinical practice., Design: Retrospective observational cohort study., Participants: Patients (N = 30 106) initiating intravitreal anti-VEGF treatment for nAMD between October 2009 and November 2016., Methods: Analysis of longitudinal electronic health records from USRetina., Main Outcome Measures: Number of intravitreal injections, OCT examinations, and fluorescein angiography (FA) examinations per study eye during the first 12 months; corrected VA and central retinal thickness (CRT) at 12 months; and number of ophthalmologist visits, stratified by index anti-VEGF agent., Results: Over the first 12 months, patients made a mean of 8.1 (range, 1-39) ophthalmologist visits, received a mean of 6.0 (range, 1-27) anti-VEGF injections, and underwent 7.2 OCT and 5.3 FA examinations per study eye. For eyes with paired baseline and 12-month readings, mean CRT declined from 320 to 271 μm (mean change, -48 μm), and mean VA increased from 60.3 to 61.0 approximate Early Treatment Diabetic Retinopathy Study (ETDRS) letters (mean change, +0.6 letters). Twelve months after initiating index treatment with bevacizumab, ranibizumab, and aflibercept, 19.3%, 15.8%, and 15.5% of eyes, respectively, showed greater than 10-letter gain, whereas 13.2%, 14.7%, and 14.4% of eyes, respectively, showed greater than 10-letter loss. Mean change from baseline VA at 12 months increased linearly with cumulative anti-VEGF injection count: +1.79 versus -0.95 approximate ETDRS letters for eyes receiving 7 or more injections versus fewer than 7 injections. Similarly, the magnitude of the reduction from baseline CRT at 12 months tended to increase linearly with increasing number of anti-VEGF injections. Multivariate linear regression analysis, adjusted for covariates, indicated a significant association between cumulative number of anti-VEGF injections and change from baseline in VA at 12 months, with each unit increase producing an estimated gain of 0.37 approximate ETDRS letters., Conclusions: This analysis of combined morphologic and functional outcomes of anti-VEGF therapy, the largest conducted to date in nAMD, identified relatively low anti-VEGF injection frequencies, coupled with moderate anatomic and limited VA improvements, in United States clinical practice., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

We describe a novel stacked split-ring type microwave (MW) resonator that is integrated into a 10mm by 10mm sized microfluidic chip. A straightforward and scalable batch fabrication process renders the chip suitable for single-use applications. The resonator volume can be conveniently loaded with liquid sample via microfluidic channels patterned into the mid layer of the chip. The proposed MW resonator offers an alternative solution for compact in-field measurements, such as low-field magnetic resonance (MR) experiments requiring convenient sample exchange. A microstrip line was used to inductively couple MWs into the resonator. We characterised the proposed resonator topology by electromagnetic (EM) field simulations, a field perturbation method, as well as by return loss measurements. Electron paramagnetic resonance (EPR) spectra at X-band frequencies were recorded, revealing an electron-spin sensitivity of 3.7·10(11)spins·Hz(-1/2)G(-1) for a single EPR transition. Preliminary time-resolved EPR experiments on light-induced triplet states in pentacene were performed to estimate the MW conversion efficiency of the resonator., (Copyright © 2016. Published by Elsevier Inc.)

Purpose: This study sought to determine the validity of self-report of prior panretinal photocoagulation (PRP) and focal photocoagulation (FP) compared with fundus photography., Design: Prospective cohort study., Participants: One thousand three hundred sixty-three type 1 diabetic subjects from the Epidemiology of Diabetes Interventions and Complications (EDIC) study, a subset of the 1441 subjects originally enrolled in the multicenter Diabetes Control and Complications Trial., Methods: At each annual visit, subjects were asked by EDIC staff whether they had undergone PRP, FP, or both since the last completed annual clinic visit. Fundus photographs were collected from one quarter of the cohort each year and from the entire cohort at EDIC years 4 and 10. Photographs were graded for the presence and extent of PRP and FP. Seventeen years of subject reporting and photograph grading of PRP and FP were compared in EDIC subjects., Main Outcome Measures: The κ, sensitivity, specificity, and positive and negative predictive values were calculated for subject-reported PRP and FP. Factors influencing subject misreporting were investigated., Results: For subject reporting, 1244 (96%) of 1296 subjects with gradable photographs accurately reported whether they had a history of PRP in one or both eyes, and 1259 (97.5%) of 1291 with valid photographs correctly reported their history of FP. For PRP and FP, sensitivities were 90.4% and 74.0%, respectively; specificities were 96.0% and 98.8%, respectively; positive predictive values were 75.9% and 80.3%, respectively; negative predictive values were 98.9% and 98.4%, respectively; and κ values were 0.80 and 0.76, respectively. Risk factors associated with misreporting included prior laser for diabetic retinopathy and prior ocular surgery (each P<0.04)., Conclusions: For subjects with type 1 diabetes, in the absence of a clinical examination or fundus photographs, subject self-report could be a reliable tool in a well-monitored study for assessing laser treatment type in diabetic retinopathy., (Copyright © 2013 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

The incidence of cardiovascular disease, including inflammatory heart diseases like myocarditis, is increased in men. Similarly, male BALB/c mice infected with coxsackievirus B3 (CVB3) develop more severe acute inflammation in the heart compared to females. To better understand the effect of male sex hormones on cardiac inflammation, we gonadectomized (Gdx) male BALB/c mice and examined acute CVB3-induced myocarditis compared to sham controls. Viral replication in the heart was not significantly altered between Gdx and sham mice. However, gonadectomy significantly reduced testosterone levels and inflammation in the heart. FACS analysis of cell populations isolated from the heart revealed that CD11b(+) cells were significantly reduced in Gdx males. However, a GR1(+)F4/80(+) subset of CD11b(+) cells was significantly increased. Because this subset also expressed the interleukin (IL)-4R and IL-10, we refer to these cells as "alternatively activated" or M2 macrophages. A greater percentage of M2 macrophages in Gdx males expressed the inhibitory receptor Tim-3, while fewer expressed IL-1beta and IL-10. Only M2 macrophages upregulated TLR4 and Tim-3, whereas GR1(-)IL-4R(lo) macrophages did not. Additionally, IL-4(+)CD4(+) Th2 cells, Foxp3(+) regulatory T (Treg) cells and Tim-3(+)CD4(+) T cells were significantly increased in the heart following Gdx. Thus, we report for the first time that the inhibitory receptor Tim-3 is expressed on M2 macrophages. Our findings show that sex hormones and/or other mediators released from the testes inhibit anti-inflammatory populations in the heart including Tim-3(+) M2, Tim-3(+)CD4(+) T cells, Th2 and Treg resulting in more severe acute cardiac inflammation in males following CVB3 infection.

Autoimmune diseases affect approximately 8% of the population, 78% of whom are women. The reason for the high prevalence in women is unclear. Women are known to respond to infection, vaccination, and trauma with increased antibody production and a more T helper (Th)2-predominant immune response, whereas a Th1 response and inflammation are usually more severe in men. This review discusses the distribution of autoimmune diseases based on sex and age, showing that autoimmune diseases progress from an acute pathology associated with an inflammatory immune response to a chronic pathology associated with fibrosis in both sexes. Autoimmune diseases that are more prevalent in males usually manifest clinically before age 50 and are characterized by acute inflammation, the appearance of autoantibodies, and a proinflammatory Th1 immune response. In contrast, female-predominant autoimmune diseases that manifest during the acute phase, such as Graves' disease and systemic lupus erythematosus, are diseases with a known antibody-mediated pathology. Autoimmune diseases with an increased incidence in females that appear clinically past age 50 are associated with a chronic, fibrotic Th2-mediated pathology. Th17 responses increase neutrophil inflammation and chronic fibrosis. This distinction between acute and chronic pathology has primarily been overlooked, but greatly impacts our understanding of sex differences in autoimmune disease.

Purpose: To evaluate the outcomes of patients with birdshot retinochoroidopathy (BSRC) treated with corticosteroid-sparing systemic immunomodulatory therapy (IMT)., Design: Retrospective, noncomparative, interventional case series., Participants: Thirty-five patients with BSRC evaluated at the Ocular Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary from 1980 through 2003., Methods: Data on age, gender, follow-up time, delay to diagnosis or referral, treatment before and during follow-up, complications of BSRC or treatment, Snellen visual acuities (VAs), and electroretinograms (ERGs) were recorded from patient charts., Main Outcome Measures: Disease progression as determined by Snellen VAs and serial ERGs, ocular complications of BSRC or corticosteroids, and complications of systemic IMT., Results: Twenty-eight patients with a mean follow-up of 81.2 months were included. None of the patients had sufficient control of their inflammation before referral. All patients were treated with corticosteroid-sparing systemic IMT at some point during their follow-up: 92.9% were treated with cyclosporine, 67.9% with mycophenolate mofetil, 17.9% with azathioprine, 10.7% with oral methotrexate, and 7.1% with daclizumab. Ocular complications of BSRC and/or corticosteroids were cataract (53.6%), cystoid macular edema (35.7%), glaucoma (21.4%), epiretinal membrane (10.7%), and retinal detachment (3.6%). Average Snellen VAs at the time of initial visit were 0.64 (right eye) and 0.59 (left eye). Average final Snellen VAs were 0.74 (right eye) and 0.71 (left eye). (Logarithm of the minimum angle of resolution equivalents were -0.23, right eye initial; -0.19, right eye final; -0.38, left eye initial; and -0.31, left eye final.) In the right eye, 78.6% of patients and, in the left eye, 89.3% of patients had either the same or improved VA at the end of the follow-up. The 30-hertz flicker implicit time was prolonged in 58.3% of initial ERGs and in 62.5% of final ERGs. The bright scotopic amplitude was abnormal in 45.5% of initial and final ERGs., Conclusions: Long-term preservation of visual function is attainable with systemic corticosteroid-sparing IMT for patients with BSRC. Prompt treatment with systemic IMT may offer the best hope of maintaining retinal function in what is often thought of as a chronically progressive disease resistant to treatment.

Clinical evidence suggests that idiosyncratic hepatitis following administration of halogenated volatile anesthetics is mediated by autoimmune responses. No murine model to study mechanisms of anesthetic-induced or any other form of drug-induced idiosyncratic hepatitis exists. Anesthetics are believed to trigger hepatitis by covalently linking a trifluoroacetyl (TFA) chloride hapten to hepatic proteins, forming haptenated self-proteins. To test this hypothesis, we developed a hapten-induced model of hepatitis by immunization with syngeneic S100 liver proteins covalently coupled to TFA (TFA-S100). We found that TFA-S100 induced hepatitis was more severe than disease induced by S100 plus adjuvants or by the adjuvant alone and was characterized by neutrophil, mast cell, and eosinophil infiltration. TFA-specific IgG1 antibodies directly correlated with hepatitis, whereas S100 autoantibodies did not. TNF-alpha, IL-1beta, and IL-6 released from splenocytes collected 2 weeks after TFA-S100 inoculation were increased resembling the elevated serum cytokines reported in patients with autoimmune hepatitis (AIH). Three weeks after inoculation, the peak of hepatitis, we noted decreased numbers of Kupffer cells and lower levels of IL-6 and IL-10 in the liver, cytokines produced by Kupffer cells. This is the first report, to our knowledge, of a hapten-induced model of hepatitis with immune and autoimmune features.

Atherosclerosis is an inflammatory disease. The complement system plays an important role in the atherosclerotic process. However, lesser data is available on the possible role of C3 as a risk factor for atherosclerosis. Therefore, in a follow up study we determined C3 levels in 266 patients with pre-existing severe coronary artery disease (CAD) and compared their serum C3 concentrations with the cause of the disease. We investigated whether C3 levels predict the major complications of severe CAD during a 5-year long follow up period in patients, who have received an aorto-coronary bypass graft surgery. C3 concentrations were elevated in the patients with severe CAD compared to 182 healthy controls, and women had higher C3 concentrations than men. Pathological C3 levels (C3> or =1.8 g/L) were able to predict major complications of atherosclerosis (death by cardiac events, new acute myocardial infarction, stroke, carotid surgery and peripheral arterial disease) that developed during the follow up period only in women (OR: 4.1, 95% C.I. 1.23-13.61, p = 0.0249) independent of other risk factors for atherosclerosis. Our data supports the assumption that high C3 indicates the progression of atherosclerosis as a special marker of chronic inflammation.

Inflammatory fibrosis is a characteristic feature of myocarditis, dilated cardiomyopathy (DCM), and congestive heart failure. Th1-type immune responses, mediated by interleukin (IL)-12-induced interferon (IFN)-gamma, are believed to exacerbate autoimmune diseases including myocarditis. In this study, we examined the effect of IL-12R beta 1 and IFN-gamma deficiency on the development of chronic CB3-induced myocarditis using knockout mice. We found increased chronic CB3-induced myocarditis (14.1 to 43.1%, P < 0.001); pericarditis (1.5 to 7.6%, P < 0.001); fibrosis (9.7 to 27.4%, P < 0.05); and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the hearts of IFN-gamma-deficient mice. All mice infected with CB3 developed DCM, but IFN-gamma-deficient mice developed a fibrous, adhesive pericarditis associated with increased numbers of degranulating mast cells (MCs) in the pericardium (26.6 to 45.9%, P < 0.01), increased histamine levels (716 to 1930 ng/g of heart, P < 0.01), and reduced survival (100 to 43%). In contrast, IL-12R beta 1 deficiency did not significantly alter the development of chronic myocarditis. Thus, IFN-gamma protects against the development of severe chronic myocarditis, pericarditis, and DCM after CB3 infection by reducing MC degranulation, fibrosis, and the profibrotic cytokines transforming growth factor-beta(1), IL-1 beta, and IL-4 in the heart.

Purpose: To investigate the spectrum of ocular involvement, to examine the clinical outcome, and to analyze the influence of treatment in patients with chronic ocular manifestations of Reiter's syndrome (RS) referred to a tertiary care ocular immunology service., Design: Retrospective, noncomparative, interventional case series., Participants: Twenty-five patients with RS evaluated at the Ocular Immunology and Uveitis Service of the Massachusetts Eye and Ear Infirmary from 1981 through 2001., Methods: Charts of patients were reviewed and data on age, gender, follow-up time, ocular symptoms, extraocular involvement, ocular complications, therapy, and visual acuities were recorded., Main Outcome Measures: Visual acuity, ocular complications, disease progression, clinical outcome, and systemic treatment., Results: Twenty-five patients (20 male and 5 female) diagnosed with RS, with a mean age at presentation to our service of 37 years, were studied. The mean follow-up was 48.5 months. Eighty-five percent of patients tested were positive for human leukocyte antigen B27. Sixty-four percent of patients had a positive family history. All patients had oligoarthritis and enthesitis, most commonly affecting the back (56%), Achilles tendon (52%), and sacroiliac joint (24%). Eighty percent had a history of infection, most frequently urethritis (68%). Forty-four percent had a history of mucocutaneous lesions. All patients demonstrated ocular involvement at the time of diagnosis (68% with unilateral and 32% with bilateral disease), 84% had evidence of uveitis, 3% had scleritis, 2% had conjunctivitis, and 1% had pars planitis and iridocyclitis. During follow-up, the ocular complications included conjunctivitis (96%), anterior uveitis (92%), posterior uveitis (64%), keratitis (64%), cataract (56%), intermediate uveitis (40%), scleritis (28%), cystoid macular edema (28%), papillitis (16%), and glaucoma (16%). Systemic treatment for ocular inflammation was initiated in all patients. Ninety-six percent were treated with nonsteroidal anti-inflammatory agents. Eighty-eight percent were treated with corticosteroids, 64% requiring systemic prednisone. Immunosuppressive therapy was initiated in 52% of patients, with all receiving methotrexate. Seven patients required more than one immunosuppressive agent. The mean initial visual acuity was 20/25 in the right eye and 20/30 in the left eye. The mean final visual acuity was 20/25 in the right eye and 20/25 in the left eye., Conclusions: Reiter's syndrome may be associated with chronic recurrent ocular inflammation. Systemic therapy (including immunosuppressive treatment) typically is required to control the ocular inflammation and to prevent progressive visual loss.