Brolucizumab in recalcitrant neovascular age-related macular degeneration-real-world data in Chinese population.

This retrospective study aimed to determine the short-term efficacy and safety of brolucizumab treatment for recalcitrant neovascular age-related macular degeneration (nAMD) in a real-world setting in Taiwan. Recalcitrant nAMD patients who were treated with brolucizumab from November 2021 to August 2022 at Taipei Veterans General Hospital were included. Patients were followed for 3 months after switching to brolucizumab. The primary outcomes were changes in mean best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline to the third month. The secondary outcomes included the incidence of intraocular inflammation (IOI), proportion of patients with subretinal and intraretinal fluid (SRF and IRF), and change in pigment epithelial detachment (PED) height from baseline to the third month. The significance level was considered as p < .05 in all tests. A total of 38 patients (40 eyes) with a mean (±SD) age of 76.3 (±10.84) years were included. The baseline BCVA was 0.92±0.64 logMAR, and the CRT and PED height were 329.0±171.18 and 189.8±114.94 um, respectively. The patients had a significant reduction in CRT and resolution of IRF and SRF from baseline to the third month. There were numerical improvements in mean BCVA and PED height, but they were not significant. The percentages of achieving at least 0.1, 0.2, and 0.3 logMAR (equivalent to 5, 10, 15 ETDRS letters) visual gain were 50%, 37.5%, and 30%, respectively, during the first 3 months of follow-up. No IOI occurred in these patients. This study demonstrated that brolucizumab had good short-term structural and functional efficacy in recalcitrant nAMD patients.

Total Tau Protein Mediates the Association of Ischemic Cerebrovascular Disease with Cognitive Decline.

Background: Patients with transient ischemic attack (TIA) or ischemic stroke demonstrate an increased risk of cognitive dysfunction. Accumulating evidence indicates that ischemic cerebrovascular disease (ICVD) may interact with the amyloid/tau/neurodegeneration (AT[N]) biomarkers to promote dementia. However, the precise pathological mechanisms remain to be fully characterized. Objective: To elucidate the interrelationships among ICVD, ATN biomarkers in cerebrospinal fluid (CSF), and cognition. Methods: A total of 2524 participants were recruited from the CABLE study. ICVD referred to TIA/ischemic stroke. Cognitive performance was assessed by China Modified Mini-Mental State Examination (CM-MMSE) and Montreal Cognitive Assessment-b (MoCA-b). Multivariate linear regression analyses were performed to evaluate the associations of ICVD with CSF ATN biomarkers and cognition. Causal mediation analyses were used to identify whether the association was mediated by ATN biomarkers. Results: ICVD was associated with higher total-tau (t-tau) (p = 2.828×10-2) and poorer cognition (CM-MMSE: p = 1.539×10-5, MoCA-b: p = 4.552×10-6). Additionally, no discernible correlation surfaced between ICVD and amyloid-ß (Aß) 42 (p = 6.910×10-1) or phosphorylated tau (p-tau) (p = 4.324×10-1). The influence of ICVD on cognitive function was partially mediated by CSF t-tau (CM-MMSE: proportion: 2.74%, MoCA-b: proportion: 2.51%). Subgroup analyses revealed the influences of t-tau were especially evident in male (CM-MMSE: proportion: 5.45%, MoCA-b: proportion: 5.38%) and mid-life group (CM-MMSE: proportion: 9.83%, MoCA-b: proportion: 5.31%). Conclusions: These results delineated t-tau as a potential mediator for the influence of ICVD on cognition. Targeting brain ischemia and alleviating neuronal injury induced by ischemia may be a promising approach for preventing cognitive decline.

Exome sequencing and genome-wide association analyses unveils the genetic predisposition in hydroxychloroquine retinopathy.

OBJECTIVES: To unveil the candidate susceptibility genes in chloroquine/hydroxychloroquine (CQ/HCQ) retinopathy using whole exome sequencing (WES) and genome-wide association study (GWAS). METHODS: Patients with a diagnosis of CQ/HCQ retinopathy based on the comprehensive demographic and ocular examination were included. The peripheral blood was extracted for WES and GWAS analyses. The Chinese Han Southern database from 1000 genomes was used as control group to compare the affected percentage. Multivariate logistic regression analysis adjusted for age, HCQ dose, duration and renal disease were used to analyze the correlation between genetic variants and visual outcome. A poor vision outcome was defined as visual acuity <6/12. An abnormal anatomical outcome was defined as disruption of ellipsoid zone in the fovea. RESULTS: Twenty-nine patients with an average age of 60.9 ± 13.4 years, treatment duration of 12.1 ± 6.2 years, daily dose of 8.5 ± 4.1 mg/kg, and the cumulative dose of 1637.5 ± 772.5 g, were genotyped. Several candidate genes associated with CQ/HCQ retinopathy were found, including RP1L1, RPGR and RPE65, with a difference of affected percentage over 50% in mutation between the case and control groups. New foci in CCDC66: rs56616026 (OR = 63.43, p = 1.63 × 10-8) and rs56616023 (OR = 104.7, p = 5.02 × 10-10) were identified significantly associated with HCQ retinopathy. Multivariate analysis revealed increased genetic variants were significantly associated with poor functional (OR = 1.600, p = 0.004) and structural outcome (OR = 1.318, p = 0.043). CONCLUSIONS: Several candidate susceptibility genes including RP1L1, RPGR, RPE65 and CCDC66 were identified to be associated with CQ/HCQ retinopathy. In addition to disease susceptibility, patients with increased genetic variants are more vulnerable to poor visual outcomes.

Associations of Frailty with Neuropsychiatric Symptoms of Alzheimer's Disease: A Longitudinal Study.

Background: Frailty is a vulnerability state increasing the risk of many adverse health outcomes, but little is known about the effects of frailty on neuropsychiatric health. Objective: To explore the associations between frailty and the risk of neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD), especially in its different clinical stages. Methods: We included 2,155 individuals assessed using modified frailty index-11 (mFI-11), Neuropsychiatric Inventory (NPI) and Neuropsychiatric Inventory Questionnaire (NPI-Q) in the Alzheimer's Disease Neuroimaging Initiative (ADNI). The relationships between frailty and NPSs were explored with logistic regression models and Cox proportional hazard regression models. Causal mediation analyses were conducted to explore the mediation factors between frailty and NPSs. Results: Among mild cognitive impairment (MCI) participants, frailty was cross-sectionally associated with an increased risk of apathy, and longitudinally associated with increased risk of depression and apathy. Among AD participants, frailty was cross-sectionally associated with increased risk of depression and anxiety, and longitudinally associated with an increased risk of apathy. Among participants with cognitive progression, frailty was associated with increased risk of depression and apathy. In MCI participants, the influence of frailty on NPSs was partially mediated by hippocampus volume, whole brain volume, and monocytes, with mediating proportions ranging from 8.40% to 9.29%. Conclusions: Frailty was associated with NPSs such as depression, anxiety, and apathy among MCI, AD, and cognitive progression participants. Atrophy of the hippocampus and whole brain, as well as peripheral immunity may be involved in the potential mechanisms underlying the above associations.

Genetic susceptibility modifies the association of long-term air pollution exposure on Parkinson's disease.

Inconsistent findings exist regarding the potential association between polluted air and Parkinson's disease (PD), with unclear insights into the role of inherited sensitivity. This study sought to explore the potential link between various air pollutants and PD risk, investigating whether genetic susceptibility modulates these associations. The population-based study involved 312,009 initially PD-free participants with complete genotyping data. Annual mean concentrations of PM2.5, PM10, NO2, and NOx were estimated, and a polygenic risk score (PRS) was computed to assess individual genetic risks for PD. Cox proportional risk models were employed to calculate hazard ratios (HR) and 95% confidence intervals (CI) for the associations between ambient air pollutants, genetic risk, and incident PD. Over a median 12.07-year follow-up, 2356 PD cases (0.76%) were observed. Compared to the lowest quartile of air pollution, the highest quartiles of NO2 and PM10 pollution showed HRs and 95% CIs of 1.247 (1.089-1.427) and 1.201 (1.052-1.373) for PD incidence, respectively. Each 10 µg/m3 increase in NO2 and PM10 yielded elevated HRs and 95% CIs for PD of 1.089 (1.026-1.155) and 1.363 (1.043-1.782), respectively. Individuals with significant genetic and PM10 exposure risks had the highest PD development risk (HR: 2.748, 95% CI: 2.145-3.520). Similarly, those with substantial genetic and NO2 exposure risks were over twice as likely to develop PD compared to minimal-risk counterparts (HR: 2.414, 95% CI: 1.912-3.048). Findings suggest that exposure to air contaminants heightens PD risk, particularly in individuals genetically predisposed to high susceptibility.

Exploring the multifaceted impact of lanthanides on physiological pathways in human breast cancer cells.

Lanthanum (La) and cerium (Ce), rare earth elements with physical properties similar to calcium (Ca), are generally considered non-toxic when used appropriately. However, their ions possess anti-tumor capabilities. This investigation explores the potential applications and mechanisms of LaCl3 or CeCl3 treatment in triple-negative breast cancer (TNBC) cell lines. TNBC, characterized by the absence of estrogen receptor (ERα), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression, is prone to early metastasis and resistant to hormone therapy. Our results demonstrate that La/Ce treatment reduces cell growth, and when combined with cisplatin, it synergistically inhibits cell growth and the PI3K/AKT pathway. La and Ce induce oxidative stress by disrupting mitochondrial function, leading to protein oxidation. Additionally, they interfere with protein homeostasis and induce nucleolar stress. Furthermore, disturbance in F-actin web formation impairs cell migration. This study delves into the mechanism by which calcium-like elements La and Ce inhibit breast cancer cell growth, shedding light on their interference in mitochondrial function, protein homeostasis, and cytoskeleton assembly.

Associations between liver function and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in non-demented adults: The CABLE study.

Liver function has been suggested as a possible factor in the progression of Alzheimer's disease (AD) development. However, the association between liver function and cerebrospinal fluid (CSF) levels of AD biomarkers remains unclear. In this study, we analyzed the data from 1687 adults without dementia from the Chinese Alzheimer's Biomarker and LifestylE study to investigate differences in liver function between pathological and clinical AD groups, as defined by the 2018 National Institute on Aging-Alzheimer's Association Research Framework. We also examined the linear relationship between liver function, CSF AD biomarkers, and cognition using linear regression models. Furthermore, mediation analyses were applied to explore the potential mediation effects of AD pathological biomarkers on cognition. Our findings indicated that, with AD pathological and clinical progression, the concentrations of total protein (TP), globulin (GLO), and aspartate aminotransferase/alanine transaminase (ALT) increased, while albumin/globulin (A/G), adenosine deaminase, alpha-L-fucosidase, albumin, prealbumin, ALT, and glutamate dehydrogenase (GLDH) concentrations decreased. Furthermore, we also identified significant relationships between TP (ß = -0.115, pFDR < 0.001), GLO (ß = -0.184, pFDR < 0.001), and A/G (ß = 0.182, pFDR < 0.001) and CSF ß-amyloid1-42 (Aß1-42 ) (and its related CSF AD biomarkers). Moreover, after 10 000 bootstrapped iterations, we identified a potential mechanism by which TP and GLDH may affect cognition by mediating CSF AD biomarkers, with mediation effect sizes ranging from 3.91% to 16.44%. Overall, our results suggested that abnormal liver function might be involved in the clinical and pathological progression of AD. Amyloid and tau pathologies also might partially mediate the relationship between liver function and cognition. Future research is needed to fully understand the underlying mechanisms and causality to develop an approach to AD prevention and treatment approach.

Same-Day Bilateral Intravitreal Dexamethasone Implants for the Treatment of Diabetic Macular Edema.

INTRODUCTION: The aim of this study was to evaluate the outcomes and complications associated with the use of same-day bilateral intravitreal dexamethasone (DEX) implants for the treatment of diabetic macular edema (DME). METHODS: This retrospective analysis of an open-label, multicenter, consecutive case series included 130 eyes of 65 patients with bilateral DME who were treated with intravitreal DEX implants. The patients were divided into two groups: a control group (comprising 40 eyes treated with an alternating unilateral regimen) and a study group (comprising 90 eyes treated with concomitant bilateral DEX implants). All patients were followed up monthly after implantation. The changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline to sixth month after implantation, and ocular adverse effects such as intraocular pressure, cataract, and tolerability of bilateral implantation were reviewed. The primary endpoint was to assess the safety of the same-day bilateral treatment protocol. The secondary endpoints focused on evaluating the functional and anatomical changes associated with bilateral simultaneous or alternating implantations. RESULTS: At 6 months after implantation, mean BCVA increased and CRT decreased in both groups. Moreover, no serious ocular adverse effects were observed. In addition, no differences were observed between the two groups in the number of patients who required extra follow-up visits or the number of extra visits made in addition to the treatment schedule. CONCLUSIONS: Same-day bilateral intravitreal DEX implants are associated with a low complication rate and are well tolerated by patients. This safe practice may optimize efficiency and reduce the burden on both the health-care system and patients, when used to treat bilateral DME.

Efficacy and safety profile of intravitreal dexamethasone implant versus antivascular endothelial growth factor treatment in diabetic macular edema: a systematic review and meta-analysis.

To better understand the efficacy of intravitreal dexamethasone implant (Ozurdex) versus antivascular endothelial growth factor (anti-VEGF) treatment in patients with diabetic macular edema (DME). A systematic review and meta-analysis. The study included randomized control trials (RCTs) and non-randomized control trials (Non-RCTs) before December 2021 that compare the efficacy of Ozurdex-related therapyand anti-VEGF therapy. We searched PubMed, Cochrane Library, and EMBASE. The quality of the included studies was assessed carefully. 30 studies were included. Regarding BCVA change, the overall result revealed no significant differences between Ozurdex and anti-VEGF therapies in patients with nonresistant DME, but Ozurdex group had significantly more VA improvement than anti-VEGF therapies in patients with resistant DME (MD 0.12, 95% CI 0.02-0.21). In terms of central retinal thickness (CRT) decrease, there was a significant difference between Ozurdex therapy and anti-VEGF therapy in patients with nonresistant DME (MD 48.10, 95% CI 19.06-77.13) and resistant DME (MD 65.37, 95% CI 3.62-127.13). Overall, Ozurdex therapy resulted in significantly greater VA improvement and CRT decrease than anti-VEGF therapy in resistant DME patients. Ozurdex therapy was not inferior to anti-VEGF therapy in patients with nonresistant DME.

Plasma ß2-microglobulin and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact older adults: the CABLE study.

BACKGROUND: Previous studies have suggested a correlation between elevated levels of ß2-microglobulin (B2M) and cognitive impairment. However, the existing evidence is insufficient to establish a conclusive relationship. This study aims to analyze the link of plasma B2M to cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarkers and cognition. METHODS: To track the dynamics of plasma B2M in preclinical AD, 846 cognitively healthy individuals in the Chinese Alzheimer's Biomarker and LifestylE (CABLE) cohort were divided into four groups (suspected non-AD pathology [SNAP], 2, 1, 0) according to the NIA-AA criteria. Multiple linear regression models were employed to examine the plasma B2M's relationship with cognitive and CSF AD biomarkers. Causal mediation analysis was conducted through 10,000 bootstrapped iterations to explore the mediating effect of AD pathology on cognition. RESULTS: We found that the levels of plasma B2M were increased in stages 1 (P = 0.0007) and 2 (P < 0.0001), in contrast to stage 0. In total participants, higher levels of B2M were associated with worse cognitive performance (P = 0.006 for MMSE; P = 0.012 for MoCA). Moreover, a higher level of B2M was associated with decreases in Aß1-42 (P < 0.001) and Aß1-42/Aß1-40 (P = 0.015) as well as increases in T-tau/Aß1-42 (P < 0.001) and P-tau/Aß1-42 (P < 0.001). The subgroup analysis found B2M correlated with Aß1-42 in non-APOE ε4 individuals (P < 0.001) but not in APOE ε4 carriers. Additionally, the link between B2M and cognition was partially mediated by Aß pathology (percentage: 8.6 to 19.3%), whereas tau pathology did not mediate this effect. CONCLUSIONS: This study demonstrated the association of plasma B2M with CSF AD biomarkers as well as a possible important role of Aß pathology in the association between B2M and cognitive impairment, particularly in cognitively normal individuals. The results indicated that B2M could be a potential biomarker for preclinical AD and might have varied functions throughout various stages of preclinical AD progression.

Gallium maltolate shows synergism with cisplatin and activates nucleolar stress and ferroptosis in human breast carcinoma cells.

PURPOSE: Breast cancer is the most common cancer in women. Triple-negative breast cancer (TNBC) is an aggressive disease with poor outcomes. TNBC lacks effective targeted treatments, and the development of drug resistance limits the effectiveness of chemotherapy. It is crucial to identify new drugs that can enhance the efficacy of traditional chemotherapy to reduce drug resistance and side effects. METHODS: TNBC cell lines, MDA-MB-231 and Hs 578T, and a normal cell line, MCF-10 A, were included in this study. The cells were treated with gallium maltolate (GaM), and their transcriptome was analyzed. Ferroptosis and nucleolar stress markers were detected by qPCR, western blotting, fluorescence microscopy, and flow cytometry. The impairment of ribosome synthesis was evaluated by northern blotting and sucrose gradients. RESULTS: GaM triggered cell death via apoptosis and ferroptosis. In addition, GaM impaired translation and activated nucleolar stress. Cisplatin (DDP) is a chemotherapeutic agent for advanced breast cancer. While single treatment with GaM or DDP at low concentrations did not impact cell growth, co-administration enhanced cell death in TNBC but not in normal breast cells. The enhancement of ferroptosis and nucleolar stress could be observed in TNBC cell lines after co-treatment. CONCLUSIONS: These results suggest that GaM synergizes with cisplatin via activation of nucleolar stress and ferroptosis in human breast carcinoma cells. GaM is marginally toxic to normal cells but impairs the growth of TNBC cell lines. Thus, GaM has the potential to be used as a therapeutic agent against TNBC.

Reconstructing the portal vein through a posterior pancreatic tunnel: New choice for portal vein thrombosis during liver transplantation.

BACKGROUND: Thrombectomy and anatomical anastomosis (TAA) has long been considered the optimal approach to portal vein thrombosis (PVT) in liver transplantation (LT). However, TAA and the current approach for non-physiological portal reconstructions are associated with a higher rate of complications and mortality in some cases. AIM: To describe a new choice for reconstructing the portal vein through a posterior pancreatic tunnel (RPVPPT) to address cases of unresectable PVT. METHODS: Between August 2019 and August 2021, 245 adult LTs were performed. Forty-five (18.4%) patients were confirmed to have PVT before surgery, among which seven underwent PV reconstruction via the RPVPPT approach. We retrospectively analyzed the surgical procedure and postoperative complications of these seven recipients that underwent PV reconstruction due to PVT. RESULTS: During the procedure, PVT was found in all the seven cases with significant adhesion to the vascular wall and could not be dissected. The portal vein proximal to the superior mesenteric vein was damaged in one case when attempting thrombolectomy, resulting in massive bleeding. LT was successfully performed in all patients with a mean duration of 585 min (range 491-756 min) and mean intraoperative blood loss of 800 mL (range 500-3000 mL). Postoperative complications consisted of chylous leakage (n = 3), insufficient portal venous flow to the graft (n = 1), intra-abdominal hemorrhage (n = 1), pulmonary infection (n = 1), and perioperative death (n = 1). The remaining six patients survived at 12-17 mo follow-up. CONCLUSION: The RPVPPT technique might be a safe and effective surgical procedure during LT for complex PVT. However, follow-up studies with large samples are still warranted due to the relatively small number of cases.

Sleep duration and risk of cardio-cerebrovascular disease: A dose-response meta-analysis of cohort studies comprising 3.8 million participants.

Background: The effect of extreme sleep duration on the risk of cardiovascular and cerebrovascular diseases (CCDs) remains debatable. The pathology of CCDs is consistent in some respects (e.g., vascular factors), suggesting that there may be an overlapping range of sleep duration associated with a low risk of both diseases We aimed to quantify the dose-response relationship between sleep duration and CCDs. Study objective: To explore whether there is an optimal sleep duration (SD) in reducing the risk of CCDs. Methods: PubMed and EMBASE were searched until June 24, 2022 to include cohort studies that investigated the longitudinal relationships of SD with incident CCDs, including stroke and coronary heart disease (CHD). The robusterror meta-regression model (REMR model) was conducted to depict the dose-response relationships based on multivariate-adjusted risk estimates. Results: A total of 71 cohorts with 3.8 million participants were included for meta-analysis, including 57 for cardiovascular diseases (CVD) and 29 for cerebrovascular disease. A significant U-shaped relationship was revealed of nighttime sleep duration with either cardiovascular or cerebrovascular disease. The nighttime sleep duration associated with a lower risk of CVD was situated within 4.3-10.3 h, with the risk hitting bottom at roughly 7.5 h per night (p non-linearity < 0.0001). Sleep duration associated with a lower risk of cerebrovascular diseases ranges from 5 to 9.7 h per night, with the inflection at 7.5 h per night (p non-linearity = 0.05). Similar non-linear relationship exited in daily sleep duration and CCDs. Other subgroup analyses showed non-linear relationships close to the above results. Conclusion: Rational sleep duration (7.5 h/night) is associated with a reduced risk of cardio-cerebrovascular disease for adults.

Clinical manifestation and current therapeutics in X-juvenile retinoschisis.

X-linked juvenile retinoschisis (XLRS) is one of the common early-onset hereditary retinal degenerative diseases in men. The common symptoms of XLRS range from mild to severe central vision loss and radial stripes created by the fovea, the division of the inner layer of the retina in the peripheral retina and the significant decrease in b-wave amplitude (ERG). Retinoschisin, the 224-amino-acid protein product of the retinoschisis 1 (RS1) gene, contains a discoid domain as the primary structural unit, an N-terminal cleavable signal sequence, and an oligomerization-area component. Retinoschisin is a homo-octamer complex with disulfide links that are released by retinal cells. It helps preserve the retina's integrity by binding to the surface of photoreceptors and bipolar cells. As a recessive genetic disease, XLRS was usually treated by prescribing low vision aids in most clinical cases. A gene replacement therapy based on adeno-associated virus vectors was initiated and showed a breakthrough in treating XLRS in 2014. Understanding the revolution of gene therapy for treating XLRS may accelerate its development and make this gene therapy the template for developing therapeutics against other inherited retinal diseases.

FACTORS RELATED TO UNFAVORABLE VISUAL OUTCOME AFTER IDIOPATHIC EPIRETINAL MEMBRANE SURGERY IN PATIENTS WITH GLAUCOMA.

PURPOSE: To evaluate the visual outcomes after idiopathic epiretinal membrane surgery in glaucomatous and nonglaucomatous eyes and factors related to unfavorable outcomes in glaucomatous eyes. METHODS: This was a retrospective cohort study including patients undergoing idiopathic epiretinal membrane surgery with ≥12-month follow-up. Final visual acuity at pseudophakic status was compared among groups of glaucoma, glaucoma suspect, and nonglaucoma and correlated with optical coherence tomography and visual field characteristics in patients with glaucoma. RESULTS: Of the 314 patients enrolled, 31 had glaucoma and 22 were glaucoma suspect. Baseline visual acuity and central foveal thickness were similar across the groups. Most patients had improved/stable visual acuity postoperatively, with a lower proportion of 83.9% with glaucoma than 96.9% and 100% without glaucoma and glaucoma suspect, respectively (P = 0.002). The mean visual acuity did not change in the glaucoma group (from 6/29 to 6/23), but it improved from 6/25 to 6/12 (a gain of 16.7 approxETDRS letters) in nonglaucoma and 6/26 to 6/14 in glaucoma suspect (a gain of 14.0 approxETDRS letters) (both P < 0.001). The change of visual acuity was correlated with preoperative visual field defects (P < 0.001, r2 = 0.554). Patients with glaucoma with more advanced, fixation-threatening defects or temporally located inner nuclear layer microcysts were more likely to have worsened visual acuity. CONCLUSION: Visual field testing is imperative for patients with glaucoma before idiopathic epiretinal membrane surgery for outcome assessment.

The first reported case of trastuzumab induced interstitial lung disease associated with anti-neutrophil cytoplasmic antibody vasculitis - A case report and a prospective cohort study on the usefulness of neutrophil derived biomarkers in monitoring vasculitis disease activity during follow-up.

Targeted therapies against human epidermal growth factor receptor 2 (HER2) are associated with increased interstitial lung disease (ILD). Trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine have markedly extended HER2 breast cancer survival but current knowledge on how these HER2-targeted agents induce interstitial lung disease is still poorly defined due to limited cases in the literature. Physicians mostly managed this complication by dose interruption, dose de-escalation, or discontinuation with success. In 2019, the FDA had granted accelerated approval on trastuzumab deruxtecan (T-Dxd) in HER2 breast cancer in the late line setting. Severe ILD incidence rate was over ten percent and led to fatal outcomes in 2.2% of patients in the T-Dxd trial. Searching for biomarkers to detect ILD incidence before it becomes clinically fulminant or for treatment response monitoring is of high clinical value. A Case of life-threatening trastuzumab-induced ILD was encountered in our facility. The ILD was confirmed to be antineutrophil cytoplasmic antibody (ANCA) pulmonary capillaritis. The biomarker of neutrophil extracellular traps (NETs), serum MPO-DNA complex, showed a good correlation with the clinical severity. Soon after B cell depleting agent rituximab usage, the serum MPO-DNA outperformed ANCA autoantibody and maintained its correlation with clinical severity. In addition to the trastuzumab-induced ILD case, a prospective cohort in our facility also confirmed the usefulness of MPO-DNA in monitoring vasculitis activity. We postulated that upfront testing with biomarkers of vasculitis during HER2 targeted treatment with high ILD incidence may be beneficial in the future.

Therapeutic effect of simultaneous intravitreal dexamethasone and aflibercept on diabetic macular edema.

AIMS: To report the effect of simultaneous intravitreal dexamethasone (DEX) and aflibercept for the treatment of diabetic macular edema (DME). METHODS: This retrospective analysis of an open-label, multicenter, consecutive case series included 102 eyes of 81 patients with DME. Patients were selected into two groups. The control group consisted of 50 eyes treated with aflibercept alone, and the combination group consisted of 52 eyes treated with simultaneous DEX implant and aflibercept injection. The primary endpoints were changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT) from baseline to month 6. The secondary endpoint was the interval of retreatment. RESULTS: Baseline BCVA increased and CRT decreased at 6 months in both groups. Pseudophakic eyes in the combination group exhibited significantly greater BCVA improvement compared with phakic eyes (p = 0.031). Fewer intravitreal treatments were required for eyes treated with combination therapy than for those treated with aflibercept alone (1.56 ± 0.54 vs. 4.04 ± 1.26, p < .0001), with a mean retreatment interval of 3.66 ± 0.69 months. CONCLUSIONS: Simultaneous intravitreal DEX and aflibercept achieved non-inferior improvement of visual and anatomic outcomes compared with aflibercept alone for DME, but exhibited a significantly longer treatment interval and superior visual outcome in pseudophakic eyes. This therapeutic approach is considered a valid strategy for treating DME in the era of COVID-19.

Visual outcomes and incidence of pseudophakic cystoid macular oedema in eyes with cataract and idiopathic epiretinal membrane after two-step sequential surgery.

OBJECTIVES: To determine whether pars plana vitrectomy (PPV) or cataract surgery should be performed first in concurrent epiretinal membrane (ERM) and cataract treatment with respect to visual outcome and pseudophakic cystoid macular oedema (PCMO) incidence. METHODS: Patients who underwent PPV and cataract surgery sequentially at a tertiary medical centre were retrospectively recruited. Best-corrected visual acuity (BCVA) and central macular thickness (CMT) measured from optical coherence tomography (OCT) images collected before and after each surgery were documented. OCT-defined PCMO incidence and its influence on visual outcomes were analysed. RESULTS: In total, 259 and 159 eyes received PPV (ERM-CATA) before and after cataract surgery (CATA-ERM), respectively. The ERM-CATA group had better final BCVA (logMAR: 0.274 vs. 0.558, p < 0.001) and greater BCVA gain (logMAR VA change: -0.379 vs. -0.220, p = 0.001) than did the CATA-ERM group. Baseline BCVA was positively correlated with final BCVA (p < 0.001), whereas baseline CMT, final CMT, and postoperative CMT changes were not. PCMO incidence did not differ significantly between the two groups (15.4% vs. 19.5%, p = 0.287), and final BCVA changes did not significantly differ between eyes with and without PCMO. PCMO incidence was much higher (29.40% vs. 16.30%, p = 0.008) in eyes with baseline CMT ≥ 500 µm. CONCLUSIONS: When managing ERM and cataract, PPV should be performed before cataract surgery to yield better visual outcomes. Both surgical sequences yield similar PCMO rates. Greater baseline CMT is a risk factor for PCMO after cataract surgery.

Identification of Novel Genomic-Variant Patterns of OR56A5, OR52L1, and CTSD in Retinitis Pigmentosa Patients by Whole-Exome Sequencing.

Inherited retinal dystrophies (IRDs) are rare but highly heterogeneous genetic disorders that affect individuals and families worldwide. However, given its wide variability, its analysis of the driver genes for over 50% of the cases remains unexplored. The present study aims to identify novel driver genes, disease-causing variants, and retinitis pigmentosa (RP)-associated pathways. Using family-based whole-exome sequencing (WES) to identify putative RP-causing rare variants, we identified a total of five potentially pathogenic variants located in genes OR56A5, OR52L1, CTSD, PRF1, KBTBD13, and ATP2B4. Of the variants present in all affected individuals, genes OR56A5, OR52L1, CTSD, KBTBD13, and ATP2B4 present as missense mutations, while PRF1 and CTSD present as frameshift variants. Sanger sequencing confirmed the presence of the novel pathogenic variant PRF1 (c.124_128del) that has not been reported previously. More causal-effect or evidence-based studies will be required to elucidate the precise roles of these SNPs in the RP pathogenesis. Taken together, our findings may allow us to explore the risk variants based on the sequencing data and upgrade the existing variant annotation database in Taiwan. It may help detect specific eye diseases such as retinitis pigmentosa in East Asia.