Cancer-Derived Succinate Promotes Macrophage Polarization and Cancer Metastasis via Succinate Receptor.

Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.

BROAD VITREOMACULAR ATTACHMENT-INDUCED MACULAR HOLE: Structural Changes and Surgical Outcome.

PURPOSE: This study aims to describe the structural changes and surgical outcomes of full-thickness macular holes (FTMHs) induced by vitreomacular traction with broad vitreomacular attachment (VMA). METHODS: A retrospective analysis of idiopathic FTMHs from October 2010 to May 2022 was conducted. Patients with FTMHs and no retinal detachment (RD) induced by broad VMA (the study group) were compared with a control group consisting of typical FTMHs with focal VMA. RESULTS: Thirty-one eyes had broad VMA-associated FTMH, among which seven eyes (22%) were with concurrent RD. Among the total of 24 cases without RD, 8 (33%) exhibited schisis. The incidence of lamellar holes associated epithelial proliferation and multiple membrane traction was significantly higher in the study group. One hundred percent FTMH closure was observed postoperatively in both groups. Although the postoperative visual acuity was not significantly different, the study group showed a greater ellipsoid zone disruption length. CONCLUSION: Broad VMA-induced FTMHs are characterized by diverse macular structural changes, including schisis and macular detachment. These FTMHs are associated with a higher incidence of lamellar holes associated epithelial proliferation and multiple membrane traction. Surgical outcomes for FTMHs induced by broad VMA are similar to those induced by typical focal VMA, with both groups demonstrating a 100% hole-closure rate.

Genetics in neovascular age-related macular degeneration susceptibility and treatment response to anti-VEGF intravitreal injection: A case series study.

BACKGROUND: To identify genotypes associated with neovascular age-related macular degeneration (nAMD) and investigate the associations between genotype variations and anti-vascular endothelial growth factor (VEGF) treatment response. METHODS: This observational, retrospective, case series study enrolled patients diagnosed with nAMD who received anti-VEGF treatment in National Taiwan University Hospital with at least one-year follow-up between 2012 and 2020. A genome-wide association study (GWAS) was conducted on enrolled patients and controls. Correlations between the genotypes identified from GWAS and the treatment response of functional/anatomical biomarkers, including visual acuity (VA), presence of intraretinal or subretinal fluid (SRF), serous or fibrovascular pigmented epithelium detachment (PED), and disruption of the ellipsoid zone (EZ), were analysed. RESULTS: In total, 182 patients with nAMD and 1748 controls were enrolled. GWAS revealed 16 single nucleotide polymorphisms (SNPs) as risk loci for nAMD, including seven loci in CFH and ARMS2/HTRA1 and nine novel loci, including rs117517872 and rs79835234(COPB2-DT), rs7525578(RAP1A), rs2123738(LOC105376755), rs1374879(CNTN3), rs3812692(SAR1A), rs117501587(PRKCA), rs9965945(CNDP1), and rs189769231(MATK). Our study revealed rs800292(CFH), rs11200638(HTRA1), and rs2123738(LOC105376755) correlated with poor treatment response in VA (P = 0.005), SRF (P = 0.044), and fibrovascular PED (P = 0.007), respectively. Rs9965945(CNDP1) was correlated with poor response in disruption of EZ (P = 0.046) and serous PED (P = 0.049). CONCLUSIONS: Among the 16 SNPs found in the GWAS, four loci-CFH, ARMS2/HTRA1, and two novel loci-were correlated with the susceptibility of nAMD and anatomical/functional responses after anti-VEGF treatment.

Association between non-steroidal anti-inflammatory drug use and development of age-related macular degeneration-A 10-year retrospective cohort study.

PURPOSE: To analyze the associations between development of age-related macular degeneration (AMD) and regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs (NA-NSAIDs). METHODS: We retrospectively recruited individuals who received ≥28-day prescriptions of aspirin or NA-NSAIDs exclusively between 2008 and 2017 in one tertiary center as regular users. Non-regular users were free from regular use of any anti-inflammatory drugs and were matched to regular users in terms of age, sex, and visit date at a ratio of 1-4:1. The aspirin cohort included 36,771 regular users and 110,808 matched non-regular users, while the NA-NSAID cohort included 59,569 regular users and 179,732 matched non-regular users. Stratified multivariate Cox regression analyses with adjustment for systemic confounding factors were performed for the development of AMD and neovascular AMD. RESULTS: In the aspirin cohort, the adjusted hazard ratios of aspirin use for AMD in the whole cohort, individuals without cardiovascular diseases (CVDs), and those with CVDs were 0.664, 0.618, and 0.702, respectively (P < 0.0001 for all), while those of aspirin use for neovascular AMD were 0.486, 0.313, and 0.584 (P < 0.05 for all), respectively. In the NA-NSAID cohort, regular use of NA-NSAIDs was associated with a decreased risk of AMD (hazard ratio = 0.823, P < 0.0001) and neovascular AMD (hazard ratio = 0.720, P = 0.040) only in people without arthritis. CONCLUSIONS: Regular use of aspirin or NA-NSAIDs had protective effects on AMD and neovascular AMD. The effect of aspirin was observed in all patients, while the effect of NA-NSAIDs was observed only in people without arthritis.

RATE OF AND TIME TO COMPLETE RETINAL VASCULARIZATION IN PREMATURE INFANTS AND ASSOCIATED FACTORS.

PURPOSE: To evaluate the rate of and time to complete vascularization in premature infants and to explore associated factors. METHODS: A monocentric, retrospective cohort study including 541 premature infants who underwent screening for retinopathy of prematurity (ROP) between July 2016 and June 2019. Patients underwent regular dilated fundus examinations with indirect ophthalmoscopy until complete vascularization. The worse eye of each patient was included for analyses. The proportion of infants with complete retinal vascularization at the last visit and the time to full vascularization was analyzed. RESULTS: Among all infants (average gestational age 31.29 ± 3.12 weeks), 490 (90.57%) had complete records of retinal vascularization outcomes, of whom 439 (89.59%) achieved complete vascularization. The average postmenstrual age for complete vascularization was 45.39 ± 11.04 weeks, and 95.22% achieved completion before 64 weeks of postmenstrual age. Retinopathy of prematurity developed in 118 (22.56%) infants; 33 (6.10%) received antivascular endothelial growth factor treatment. For all infants screened for ROP, lower birth weight, presence of ROP, and antivascular endothelial growth factor therapy predicted delayed complete vascularization; for infants diagnosed with ROP, only lower birth weight predicted delayed complete vascularization. Subgroup analysis showed significant differences between patients without ROP, with untreated ROP, and with treated ROP in time to complete vascularization and its rate (99.7%, 66.2%, and 16.7%, respectively). CONCLUSION: Lower birth weight predicted delayed complete vascularization. Antivascular endothelial growth factor therapy and the presence of ROP, including ROP severity, may also affect time to complete vascularization. These findings should help improve the understanding and management of persistent avascular retina in preterm infants.

CLINICAL CHARACTERISTICS AND PROGNOSTIC FACTORS AFFECTING CLINICAL OUTCOMES IN CYTOMEGALOVIRUS RETINITIS WITH OR WITHOUT HIV INFECTION.

PURPOSE: To explore the clinical features and outcomes of cytomegalovirus retinitis (CMVR) in patients with HIV and non-HIV. METHODS: This retrospective cohort study included all patients with CMVR in National Taiwan University Hospital from 2013 to 2018. Demographic data, clinical characteristics, CMVR recurrence, and overall survival were compared between the HIV and non-HIV groups. Generalized estimating equation models were implemented to analyze the risk factors of poor visual prognosis. The Kaplan-Meier survival analysis was performed to investigate recurrence and survival. RESULTS: A total of 66 patients (95 eyes) with CMVR were enrolled, with no significant differences between the HIV (41 patients; 61 eyes) and non-HIV (25 patients; 34 eyes) groups in initial/final visual acuity, lesion area, or viral loads. Poor visual outcome was associated with poor initial visual acuity, retinal detachment, and a higher plasma cytomegalovirus titer. The HIV group had significantly longer survival rate ( P = 0.033) and lower recurrence rate ( P = 0.01) than the non-HIV group, and it also presented with better prognosis in recurrence-free survival analysis ( P = 0.01). CONCLUSION: Patients with CMVR without HIV had higher mortality and recurrence rates than the HIV group. Risk factors of poor visual outcome included poor initial visual acuity, retinal detachment, and a high plasma cytomegalovirus titer.

Associations between macular retinal vasculature and severity of idiopathic epiretinal membrane.

BACKGROUND: To demonstrate the associations between the morphology of macular retinal vasculature and disease severity of idiopathic epiretinal membrane (ERM). METHODS: Macular structures were assessed using optical coherence tomography (OCT), and were classified as "with pseudohole" or "without pseudohole". The 3 × 3 mm macular OCT angiography images were analyzed using the Fiji software to obtain the vessel density, skeleton density, average vessel diameter, vessel tortuosity, fractal dimension, and foveal avascular zone (FAZ)-related parameters. The correlations between these parameters and ERM grading as well as visual acuity were analyzed. RESULTS: For ERM with or without a pseudohole, increased average vessel diameter, decreased skeleton density, and decreased vessel tortuosity were all associated with inner retinal folding and thickened inner nuclear layer, indicating more severe ERM. In 191 eyes without a pseudohole, the average vessel diameter increased, fractal dimension decreased and vessel tortuosity decreased with increasing ERM severity. The FAZ was not associated with ERM severity. Decreased skeleton density (r = -0.37), vessel tortuosity (r = -0.35), and increased average vessel diameter (r = 0.42) were correlated with worse visual acuity (All P < 0.001). In 58 eyes with pseudoholes, a larger FAZ was associated with a smaller average vessel diameter (r = -0.43, P = 0.015), higher skeleton density (r = 0.49, P < 0.001), and vessel tortuosity (r = 0.32, P = 0.015). However, none of the retinal vasculature parameters correlated with visual acuity and central foveal thickness. CONCLUSION: Increased average vessel diameter, decreased skeleton density, decreased fractal dimension and decreased vessel tortuosity were good indicators of ERM severity and associated visual impairment.

Dilated choroidal vascular channels in pachychoroid neovasculopathy.

BACKGROUND: To elucidate the pattern of the choroidal vasculature in exudative pachychoroid neovasculopathy (PNV) and its correlation with the clinical course and treatment outcomes. METHODS: The retrospective study included consecutive patients in National Taiwan University Hospital between 2014 and 2020 who fulfilled the criteria for exudative PNV defined as active type 1 macular neovascularization (MNV) on optical coherence tomography angiography (OCTA) and with leakage on fluorescein angiography (FA) or indocyanine green angiography (ICGA) associated with pachychoroid features. The corrected distance visual acuity (CDVA), FA, ICGA, and OCT images obtained by Optovue (Optovue Inc, Freemont CA, USA) spectral domain OCT were evaluated at baseline and various time points during the 12-month treatment period. The correlations between the choroidal vascular patterns, specifically those with or without dilated choroidal vascular channels (DCVC) revealed by ICGA, and baseline characteristics and treatment outcomes were evaluated using multiple regression models. RESULTS: The study enrolled 34 eyes of 31 patients. The average age was 59.0 ± 9.3 years, and 20 participants were men. ICGA revealed DCVCs in 21 eyes, while the remaining 13 eyes did not have DCVCs. At baseline, DCVC group was older (p = 0.03) and had a longer duration of visual symptoms (p = 0.02), with a higher vessel density (defined as the percentage of the measured area occupied by flow area) of MNV (p = 0.04), higher proportion of ellipsoid zone disruption (p = 0.01), and poorer CDVA (p = 0.03). After the 12-month treatment period, the frequency of requirement of anti-VEGF injections (p < 0.01) was higher, and the risk for CDVA <20/40 was higher (adjusted OR: 5.29, 95% CI: 1.24-22.48, p = 0.02) in eyes with DCVCs. CONCLUSIONS: For PNV, eyes with DCVCs were associated with higher vessel density of macular neovascularization and poorer CDVA at baseline, and had poorer visual and anatomical outcomes although more anti-VEGF injections were given.

Detection of nitrofurazone with metal-organic frameworks and reduced graphene oxide composites: insights from molecular dynamics simulations.

Two-dimensional metal-organic framework (MOF) composites were produced by incorporating Fe-MOFs into reduced graphene oxide (rGO) nanosheets to form Fe-MOF/rGO composites by hydrothermal synthesis. SEM, TEM, XRD, XPS, and measurements of contact angles were used to characterize the composites. TEM studies revealed that the rod-like-shaped Fe-MOFs were extensively dispersed on the rGO sheets. Incorporating Fe-MOF into rGO significantly improves performance due to the large surface area, chemical stability, and high electrical conductivity. The response signals for the electrochemical sensing performance of Fe-MOF/rGO-modified electrodes to nitrofurazone (NFZ) were significantly enhanced. Differential pulse voltammetry was used to detect the NFZ, and the MOF/rGO sensor possesses a lower detection limit (0.77µM) with two dynamic ranges from 0.6-60 to 128-499.3 µM and high sensitivity (1.909 µA·mM-1·cm-2). Moreover, the anti-interference properties of the sensor were quite reproducible and stable. To understand the mechanism responsible for the enhanced sensing performance of the composite, grand canonical Monte Carlo calculations were performed for Fe-MOF/rGO composites with five unit cells of Fe-MOF and four layers of rGO. We attributed the improvement to the fact that the interface between the Fe-MOF and rGO absorbed increased NFZ molecules. The findings reported herein confirm that such Fe-MOF/rGO composites have significantly improved electrochemical performance and practical applicability of sensing nitrofurazone.

The association between retinal vascular fractal dimension and cognitive function in the community-dwelling older adults cohort TIGER.

BACKGROUND/PURPOSE: The small retinal vessels reflect cerebral microcirculation and its fractal dimension (Df), representing the complexity of the retinal microcirculation. However, the connection between retinal circulation and cognitive function lacked consistent and longitudinal evidence. This study aimed to explore the association between retinal vascular complexity and cognitive impairment over time in non-demented community-dwelling older adults. METHODS: This four-year prospective cohort study (2015-2019) is part of the ongoing Taiwan Initiative for Geriatric Epidemiological Research (TIGER, 2011 to present). Of the 434 older adults (age >65) recruited, 207 participants were included for analysis. The retinal vascular Df was assessed by baseline images from fundus photography (2015-2017). Global (Montreal Cognitive Assessment-Taiwanese version, MoCA-T) and domain-specific cognition were assessed at the baseline and 2-year follow-up (2017-2019). The multivariable linear regression models and generalized linear mixed models were used to evaluate the association of Df with cognitive decline/impairment over time. RESULTS: Decreased left retinal vascular complexity was associated with poor attention performance (ß = -0.40). As follow-up time increased, decreased vascular complexity was associated with poor memory performance (right: ß = -0.25; left: ß = -0.19), and decreased right vascular complexity was associated with poor attention performance (ß = -0.18). CONCLUSION: Low retinal vascular complexity of the right or left eye may be differentially associated with cognitive domains in community-dwelling older adults over two years. The retinal vascular Df of either eye may be served as a screening tool for detecting cognitive impairment in the preclinical phase of dementia.

Quantitative analysis of branching neovascular networks in polypoidal choroidal vasculopathy by optical coherence tomography angiography after photodynamic therapy and anti-vascular endothelial growth factor combination therapy.

PURPOSE: To study serial changes in branching neovascular networks (BNN) by using optical coherence tomography angiography (OCTA) in patients with polypoidal choroidal vasculopathy (PCV) who underwent combined photodynamic therapy (PDT) and anti-vascular endothelial growth factor (anti-VEGF) therapy. METHODS: In this retrospective study of 30 PCV patients who underwent combined therapy, OCTA images obtained at baseline and 1, 3, and 6 months after treatment were collected. The vessel area, vessel percentage area, average vessel length, and presence of polypoidal lesions on OCTA images as well as best-corrected visual acuity (BCVA), central retinal thickness (CRT), and central choroidal thickness (CCT) were recorded at each time point. RESULTS: The BNN- and polypoidal lesion-detection rates on baseline OCTA images were 100% and 71%, respectively. The vessel area decreased during the first 3 months, and increased 6 months post-treatment, showing significant differences from baseline (p = 0.031). The vessel percentage area also reduced 1 and 3 months post-treatment (p = 0.025) and increased 6 months post-treatment. Continuous polypoidal lesion regression was observed from 1 to 3 and 6 months post-treatment (p = 0.031, p = 0.004, p = 0.002, respectively, in comparison with baseline). Patients with a decreasing vessel area over 6 months showed greater choroidal thickness than those with increasing vessel area (p = 0.004). CONCLUSIONS: The BNN showed initial regression but were enlarged at 6 months after therapy. Patients showing continuous BNN regression showed a thicker choroid at baseline. This difference should be considered during treatment for PCV, and OCTA could be used for follow-up evaluations of PCV patients.

Effect of anticoagulant/antiplatelet therapy on the development and progression of diabetic retinopathy.

BACKGROUND: We investigated whether antiplatelet/anticoagulant (APAC) therapy can protect patients with type 2 diabetes mellitus (T2DM) from the development or progression of diabetic retinopathy (DR). METHODS: This is a retrospective cohort study using Longitudinal Health Insurance Database in Taiwan. A total of 73,964 type 2 diabetic patients older than 20 years old were included. Hazard ration (HR) of non-proliferative DR (NPDR), proliferative DR (PDR), and diabetic macular edema (DME) were analyzed with APAC usage as a time-dependent covariate. Age, sex, comorbidities, and medicines were further adjusted in a multi-variable model. Contributions of respective APAC was investigated with sensitivity analysis. RESULTS: Compared with nonusers, APAC users had a lower cumulative incidence of NPDR (P < 0.001), overall incidence of NPDR (10.7 per 1000 person-years), and risk of developing NPDR (adjusted HR = 0.78, 95% CI = 0.73-0.83). However, no significant differences were observed between APAC users and nonusers in the risks of PDR or DME. Hypertension, diabetic nephropathy and diabetic neuropathy were risk factors for NDPR development, while heart disease, cardiovascular disease, peripheral arterial occlusive disease, and statin usage were covariates decreasing NPDR development. Aspirin and Dipyridamole showed significant protection against NPDR development. Clopidogrel, Ticlopidine, and warfarin showed enhanced protection in combination with aspirin usage. CONCLUSIONS: APAC medications have a protective effect against NPDR development. Diabetic patients benefit from single use of aspirin or dipyridamole on prevention of NPDR.

Tight adherent feature on optical coherence tomography predict postoperative visual outcome in epiretinal membrane eyes.

BACKGROUND: To identify the predictive parameter among preoperative measurements that best predicts postoperative visual outcome in the epiretinal membrane (ERM). METHODS: Thirty-three consecutive patients with idiopathic unilateral ERM patients between 2015 and 2018 were enrolled. Nineteen healthy normal eyes were selected as an independent age-matched group. Based on preoperative optical coherence tomography (OCT), we further divided the patients with ERM into two groups: type 1, loosely attached ERM, and type 2, tight adherent ERM. We documented the vision and thickness of various retinal layers: nerve fiber layer, ganglion cell layer, inner plexiform layer (GCL + IPL), inner nuclear layer (INL), outer retinal layer (ORL), and retinal pigment epithelium/Bruch complex layer before and after the surgery. The association between postoperative visual acuity and these variables was analyzed using multiple linear regression analysis. RESULTS: All retinal layers of ERM eyes were thicker than the normal eyes (P < 0.05). Among ERMs, we identified 11 eyes with type 1 adhesions and 22 eyes with type 2 adhesions. The preoperative GCL + IPL layers were significantly thicker in type 2 patients than in type 1 patients (93.67 ± 33.03 um vs 167.71 ± 13.77 um; P = 0.023). Greater GCL + IPL thickness was correlated with a worse postoperative visual acuity and multiple linear regression analysis showed that GCL + IPL thickness was an independent predictor of postoperative visual acuity (VA) (beta value = 0.689; P = 0.012). A greater thickness of GCL + IPL layers of type 2 patients had worse postoperative best-corrected visual acuity (BCVA) (P = 0.028). Ectopic inner foveal layers with disappearance of fovea pit were persistently presented in OCT profiles of both groups. CONCLUSION: Idiopathic ERM demonstrated significantly thicker inner retinal layers (GCL + IPL and INL). However, the ORL thickness was similar between the normal eyes and ERM eyes. The preoperative GCL + IPL layers were significantly thicker in patients with type 2 ERM than that in patients with type 1 ERM. The increase in GCL + IPL thickness was significantly correlated with worse postoperative visual outcomes.

Idiopathic Macular Hole without Vitreomacular Separation.

PURPOSE: This study aimed to investigate the clinical features and treatment outcomes of idiopathic full-thickness macular hole (FTMH) without vitreomacular separation (VMS). METHODS: Consecutive cases of idiopathic FTMH at one tertiary center from January 2013 to April 2020 were retrospectively recruited. They were separated into two groups according to the findings in optical coherence tomography (OCT): FTMH with VMS and FTMH without VMS. Ophthalmic examinations and OCT were performed pre- and postoperatively. The clinical findings were compared between the two groups. RESULTS: Of the total 124 cases, 15 (12.1%) were noted as FTMH without VMS with the presence of an attached posterior hyaloid (PH) at macula. The macular hole (MH) size was smaller (276.06 ± 170.10 µm) compared to those with VMS (492.83 ± 209.31 µm) (p < 0.001). The incidence of lamellar hole-associated epiretinal proliferation (LHEP) was much higher in this group (13/15, 86.7%) compared to FTMH with VMS (11/109, 10.1%) (p < 0.001). A higher rate of spontaneous closure of MH (13.3%) was also noted in FMTH without VMS (13.3% vs. 0.9% in FTMH with VMS, p = 0.040). After operation, the MH closure rate was 93.3%. The postoperative best-corrected visual acuity was not significantly different between the two groups (p = 0.098). CONCLUSIONS: A small percentage (12.1% in this series) of idiopathic FTMH had no VMS. The completely attached PH along with the high incidence of LHEP implied a tangential traction in FTMH without VMS. The MH size was usually small, and the postoperative outcomes were similar to those of conventional FTMH with VMS.

Clinical manifestations and risk factors for poor visual outcomes of ocular sarcoidosis in Taiwan.

PURPOSE: To assess ocular involvement in sarcoidosis and to analyze the manifestations of ocular sarcoidosis (OS) in Taiwan. METHODS: A retrospective review was performed in 364 patients diagnosed as sarcoidosis at National Taiwan University Hospital from 2015 to 2019. The OS diagnosis was based on the revised criteria of International Workshop on Ocular Sarcoidosis. Demographics, clinical manifestations, treatment and effects, complications, visual outcomes and risk factors of poor vision (<20/200) were analyzed. RESULTS: A total of 122 eyes of 66 patients (13 males and 53 females) with OS were identified. Bilateral involvement accounted for 84.8%. Thirty-five patients were diagnosed with definite OS, 14 with presumed OS and 17 with probable OS. The average age was 51.9 ± 14.1 years, with no significant difference in sex. Most patients presented with panuveitis (61 eyes, 50.0%) and posterior uveitis (52 eyes, 42.6%). Systemic steroid was the mainstay treatment, and immunosuppressants or anti-metabolic agents were supplemented. Common complications included cataract (50.8%), ocular hypertension/glaucoma (25.4%) and posterior synechiae (20.5%). Forty-three eyes (36.1%) and 74 eyes (62.2%) had a final vision of 20/20 and 20/40 or better, respectively. The causes of poor visual outcome were diverse, and generalized estimating equations analysis indicated that female and poor initial vision were risk factors. CONCLUSION: Uveitis is an early sign of sarcoidosis and it might result in several complications. The overall visual outcomes were good if patients received proper treatment. Both poor initial vision and females that tended to have more severe complications were associated with poor outcome.

Sex differences in the diagnosis of autism spectrum disorder and effects of comorbid mental retardation and attention-deficit hyperactivity disorder.

BACKGROUND/PURPOSE: The association between sex and diagnostic behavior of autism spectrum disorder (ASD), and the effects of comorbid mental retardation (MR) and attention-deficit hyperactivity disorder (ADHD), were explored. METHODS: Based on the Taiwan Longitudinal Health Insurance Database (LHID)-2000 and data from 1996 through 2008, the cumulative incidence of ASD over time was compared between the sexes (both cohorts n = 38,117) using the log-rank test. The effects of comorbid MR and ADHD on the incidence of ASD were evaluated using Cox proportional hazard regression analysis. The age at first diagnosis of ASD in the two sexes was compared using the independent-sample t-test. RESULTS: The incidence was higher in males than in females (0.0007 vs. 0.0002) across ages. Comorbid MR or ADHD increased the incidence of ASD in both sexes; comorbid MR or ADHD also decreased the male to female hazard ratio of ASD, with no significant differences in the incidence density of ASD between sexes. ADHD delayed diagnosis in both sexes (males: 6.61 vs 5.10, p < 0.0001; females: 6.83 vs 4.69, p = 0.0037). CONCLUSION: The general concept of a higher incidence of ASD among males was noted in this study of a Taiwanese population, but disappeared in those with comorbid MR or ADHD, indicating unique vulnerabilities to MR/ADHD or under-identification of high-functioning females with ASD in childhood. Increasing the diagnostic sensitivity of ASD in those with comorbid ADHD is important due to a delayed diagnostic age in this group.

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.

Peripheral inflammation is associated with dysfunctional corticostriatal circuitry and executive dysfunction in bipolar disorder patients.

Bipolar disorder (BD) has been linked to abnormal frontal and striatal function, and elevated inflammatory responses. However, the impact of peripheral inflammation on the corticostriatal functional connectivity (FC) remains obscure in BD. The current study aimed to explore the association between peripheral inflammation and corticostriatal connectivity in euthymic BD. We recruited 25 euthymic BD patients and 43 healthy controls (HCs) from the community. Resting state functional images were obtained using 3T magnetic resonance imaging (fMRI), and striatal seed-based whole-brain functional connectivity analyses were performed, with the fasting plasma high-sensitivity C-reactive protein (hs-CRP) level entered as a regressor of interest. The participants also completed the Wisconsin Card-Sorting Test (WCST) and the Continuous Performance Test (CPT). The euthymic BD group had a similar hs-CRP level to the HC group, but a significantly poorer cognitive performance. Compared with the HC group, a higher connectivity between the right dorsal caudal putamen (dcP) and the ventral lateral prefrontal cortex (vlPFC) in the BD group was significantly correlated with a higher hs-CRP level. Stronger dcP-vlPFC connectivity was correlated with a lower CPT unmasked d' in the BD group. BD patients might be particularly sensitive to the effects of inflammation on corticostriatal connectivity. The potentially greater sensitivity of BD patients to peripheral inflammation may differentially modulate the cognitive and reward related corticostriatal circuitry, which may contribute to the pathophysiology of cognitive-affective dysregulation in the euthymic state. Anti-inflammatory or other circuit-specific treatment is warranted for individualized treatment in BD.

Wide-based foveal pit: a predisposition to idiopathic epiretinal membrane.

PURPOSE: To report the anatomical characteristics of wide-based foveal pit and its possible associations with macular diseases. METHODS: Wide-based foveal pit was defined as a foveal base width (FBW) larger than the mean value plus one standard deviation of the normal population. Eyes with a wide-based foveal pit were retrospectively collected as the study group, and age- and sex-matched subjects with a normal FBW were recruited as the control group. FBW, area of foveal avascular zone (FAZ), and retinal artery trajectory (RAT) were compared between the two groups. The characteristics of the fellow eyes in the study group were also described. RESULTS: Fifty-two eyes from 52 patients were identified as having a wide-based foveal pit; 43 (82.7%) were female. Both their FBW (474.7 ± 84.6 µm) and area of FAZ (0.50 ± 0.11 mm2) were significantly larger than in the control group (297.6 ± 42.3 µm and 0.29 ± 0.10 mm2, respectively; p < 0.001 for both), and they also had a wider RAT than the control group (p < 0.001). During follow-up, three eyes had developed idiopathic epiretinal membrane. As for their fellow eyes, they either also had a wide-based foveal pit (11 eyes) or had various macular diseases including idiopathic epiretinal membrane (27 eyes), macular hole (5 eyes), and others (16 eyes). CONCLUSIONS: Eyes with a wide-based foveal pit had a large FAZ and a wide RAT, and they might have a predisposition to idiopathic epiretinal membrane formation. Their fellow eyes also had a predisposition to epiretinal membrane and macular hole.

Characterization of self-anticipated pain score prior to elective surgery - a prospective observational study.

BACKGROUND: Current principles of postoperative pain management are primarily based on the types and extent of surgical intervention. This clinical study measured patient's self-anticipated pain score before surgery, and compared the anticipated scores with the actual pain levels and analgesic requirements after surgery. METHODS: This prospective observational study recruited consecutive patients who received elective surgery in the E-Da Hospital, Taiwan from June to August 2018. Patients were asked to subjectively rate their highest anticipated pain level (numeric rating scale, NRS 0-10) for the scheduled surgical interventions during their preoperative anesthesia assessment. After the operation, the actual pain intensity (NRS 0-10) experienced by the patient in the post-anesthesia care unit and the total dose of opioids administered during the perioperative period were recorded. Pain scores ≥4 on NRS were regarded as being unacceptable levels for anticipated or postoperative pain that required more aggressive intervention. RESULTS: A total of 996 patients were included in the study. Most of the patients (86%) received general anesthesia and 73.9% of them had a history of previous operation. Female anticipated significantly higher overall pain intensities than the male patients (adjusted odd ratio 1.523, 95% confidence interval 1.126-2.061; P = 0.006). Patients who took regular benzodiazepine at bedtime (P = 0.037) and those scheduled to receive more invasive surgical procedures were most likely to anticipate for higher pain intensity at the preoperative period (P < 0.05). Higher anticipated pain scores (preoperative NRS ≥ 4) were associated with higher actual postoperative pain levels (P = 0.007) in the PACU and higher total equivalent opioid use (P < 0.001) for acute pain management during the perioperative period. CONCLUSION: This observational study found that patients who are female, use regular benzodiazepines at bedtime and scheduled for more invasive surgeries anticipate significantly higher surgery-related pain. Therefore, appropriate preoperative counseling for analgesic control and the management of exaggerated pain expectation in these patients is necessary to improve the quality of anesthesia delivered and patient's satisfaction.