INTRODUCTION

Immune checkpoint inhibitors (ICIs) that target cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 receptor/ligand (PD-1/PD-L1) pathways have shown robust evidence of antitumor activity in patients with cancer. These medications include pembrolizumab,ipilimumab, nivolumab, atezolizumab, avelumab, and durvalumaband have been authorized by the Food and Drug Administration (FDA) for numerous cancer therapies. With the progressive implementation of ICIs in clinical practice,however, a key challenge has emerged: the uncontrolled collateral effects of ICIs on the immune system, which can result immune-related adverse events (irAEs) that can affect all organ systems. IrAEs comprise common adverse events,such as dermatological, gastrointestinal, hematological,pulmonary, and rheumatic toxicities, nephritis, and endocrinopathy. They also include rare adverse events (arising in ＜1% of patients), such as neurological, ocular, and cardiac toxicities, which can largely be controlled by glucocorticoid therapy. Among these toxicities, ophthalmic irAEs,including dry eye, uveitis, ocular myasthenia gravis, uveal effusion, retinal detachment, and conjunctivitis (Figure 1) occur infrequently and are not comprehensively recognized. The current understanding of ophthalmic irAEs is mainly derived from case reports and case series (Table 1). In this review,to strengthen the understanding of ICI-associated ophthalmic toxicity and enhance the quality of life of patients, we elaborate on the incidences, manifestations, diagnoses, potential mechanisms, treatments, and management of ophthalmic irAEs based on the current knowledge and relevant literature.

黨組織的思想政治工作是黨在長期的工作實(shí)踐中總結(jié)出來的重要經(jīng)驗(yàn)，是發(fā)揮黨員先鋒模范作用，促進(jìn)企業(yè)健康發(fā)展等工作的生命線。企業(yè)思想政治工作的思路是指企業(yè)思想政治工作的指導(dǎo)思想和戰(zhàn)略方針?？茖W(xué)發(fā)展觀是發(fā)展中國特色社會主義必須堅(jiān)持和貫徹的重大戰(zhàn)略思想，也是做好新形勢下思想政治工作的重要指導(dǎo)思想。近年來，中心黨總支通過加強(qiáng)黨的理論知識學(xué)習(xí)與組織建設(shè)，進(jìn)一步夯實(shí)黨建工作基礎(chǔ)，明確黨員責(zé)任，團(tuán)隊(duì)凝聚力得到了增強(qiáng)，員工創(chuàng)造力得到了激發(fā)。在廣大黨員群眾的支持下，先后榮獲了“上海市工人先鋒號”、“上海市電力公司先進(jìn)基層黨組織”等榮譽(yù)稱號。

POTENTIAL MECHANISM OF OPHTHALMIC TOXICITY

The mechanism of ICI-associated ophthalmic events has yet to be fully understood. The eyes have special mechanismsto limit the invasion of inflammation and infectious agents,thus protecting visual functionAnatomical mechanisms,such as the presence of the blood-retinal barrier and absence of efferent lymphatic vessels, protect the eyes from infection,whereas immune mechanisms, such as the upregulation of the Fas ligand and tumor growth factor-beta (TGF-β), can prevent inflammation by converting T cells into regulatory T cells and causing immune cell death.

Blockade of these regulatory T cells may trigger adverse reactions, and reprogramming of the cell death pathway may lead to ocular adverse events due to ICI therapy. To further downregulate the inflammatory T-cell activity, retinal pigment epithelial cells express both PD-L1 and CD86, which can interact with PD-l and CTLA-4, respectively. High levels of PD-L1 were also found to express in various ocular tissues and may play crucial roles in preventing autoimmunity. In addition, PD-1 and PD-L2 were expressed on tumor cells of ocular adnexal invasive squamous cell carcinomas to varying degrees; as a consequence, these tumor cells can potentially respond to ICI therapy.

IMMUNE CHECKPOINT INHIBITOR-ASSOCIATED OPHTHALMIC ADVERSE EVENTS

Ocular irAEs can occur at any time during treatment, and even after the cessation of ICIs. However, most (approximately 70%) irAEs typically occur within two months after the initiation of therapy. A minority of irAEs occurs after 48wk,and these irAEs can involve various parts of the eye and orbit. We reviewed published cases of adverse ophthalmic reactions and found that the time to onset of ophthalmic irAEs was earlier when combined with ICIs (either with other ICIs or other conventional therapies; Figure 2). Apart from the variability of the time to onset, there is variability in the ocular symptoms: the most common clinical manifestation of ICIrelated ophthalmic toxicity is dry eyes (3%-24%), uveitis(1%), and myasthenia gravis involved with the eyes (frequency undefined). Other less common ophthalmic adverse events include uveal effusion, retinal detachment, conjunctivitis,ocular myositis, vasculitis, keratitis, episcleritis, vitritis,choroidopathy, and a broad spectrum of neuro-ophthalmic toxicities (Figure 1). Information on various types of ocular adverse events are summarized in Table 2. Most of these adverse reactions can be effectively controlled by periocular,topical, or systemic corticosteroids.

以我國某一農(nóng)村為例，對農(nóng)村人畜飲水安全的影響因素進(jìn)行分析，該地區(qū)主要是利用雨水與泉水進(jìn)行供水，主要水源來自該縣的一水庫，飲水問題基本得到解決，其水質(zhì)受人為因素、環(huán)境因素、地理位置等影響極易出現(xiàn)污染，水質(zhì)不能滿足國家對生活飲水的安全標(biāo)準(zhǔn)規(guī)定，且因使用受污染的水導(dǎo)致許多村民都出現(xiàn)了骨質(zhì)疏松、糞便呈血、牙齒變黃等癥狀，嚴(yán)重威脅著村民的身體安全。通過調(diào)查發(fā)現(xiàn)，該地區(qū)的農(nóng)村人畜飲水安全影響因素主要體現(xiàn)在以下幾方面。

通過總結(jié)分析，發(fā)現(xiàn)單元教學(xué)課具有以下特色：1.注重創(chuàng)設(shè)問題情境，從生活實(shí)際或數(shù)學(xué)內(nèi)部提出問題，體現(xiàn)學(xué)習(xí)新知識的必要性。2.注重抽取分式概念的基本要素，讓學(xué)生經(jīng)歷分式概念的建構(gòu)過程，有利于培養(yǎng)學(xué)生的數(shù)學(xué)抽象概括能力。3.注重溫故知新，借助類比的方法，構(gòu)建分式內(nèi)容的整體框架。4.注重設(shè)計(jì)各類活動，拓展數(shù)學(xué)學(xué)習(xí)方式，展示分式內(nèi)容的學(xué)習(xí)成效。5.注重?cái)?shù)學(xué)思想方法的滲透，依托類比與轉(zhuǎn)化，解決新知識的學(xué)習(xí)方法問題。6.注重反思與總結(jié)，從數(shù)學(xué)學(xué)習(xí)的過程與活動中撈足“油水”，積累豐富的學(xué)習(xí)經(jīng)驗(yàn)。

Ophthalmic adverse events have been reported most frequently with ipilimumab, followed by nivolumab and pembrolizumab and subsequently by atezolizumab, avelumab, and durvalumab. The incidence of ICI-associated ocular side events is ＜1%. A total of 15 cases of ocular toxicities were reported in a series of 1474 cases who were treated with nivolumab with or without ipilimumab. A prospective cohort study recently attempted to explore the relationship between ICIs and ocular adverse events in 745 patientsand observed intraocular inflammation in 5 cases, ocular surface disease in 2 cases, and orbital myopathy in 1 case. One study has shown that patients receiving ICIs as therapy who developed colitis were also susceptible to episcleritis or uveitis.

Dry eye disease is a presentation that is characterized by tear hyperosmolarity, tear-film instability,ocular surface inflammation, and damage due to reduced tear quantity and/or quality. Dry eye disease associated with ICIs was the first and the most frequently reported ocular surface adverse event with an incidence ranging from 3% to 24%and presenting with nonspecific eye irritation and as a part of the sicca syndrome. It can also lead to corneal perforation. ICI-related dry eyes can be effectively managed with topical cyclosporine and artificial tears. One patient had nivolumab-associated corneal graft rejection and did not respond well to systemic or subconjunctival corticosteroids.Uveitis refers to the inflammation of the uvea, a highly vascularized layer between the retina and sclera. Among all ophthalmic toxicities, uveitis is one of the most common adverse reactions. It is associated with anti-CTLA-4 and anti-PD-1/PD-L1 agents, such as ipilimumab, durvalumab,avelumab, pembrolizumab, nivolumab, and atezolizumab.

Vogt-Koyanagi-Harada (VKH) disease, known as a bilateral diffuse granulomatous uveitis, is diagnosed in patients who receive anti-PD-1 agents. It presents with blurry vision,xanthopsia, and exudative retinal detachments with bilateral uveitis and is amenable to systemic and occasional topical corticosteroid therapy.

Myasthenia gravis involved with the eye is the most frequently reported adverse event of orbital and ocular adnexa. It can present with blepharoptosis,ocular motility abnormalities, diplopia, or severe systemic symptoms in addition to respiratory distress. These symptoms can be managed with oral/intravenous corticosteroids,intravenous immunoglobulin, pyridostigmine, and plasmapheresis.Severe consequences, such as death from respiratory failure,have also been recorded.

Patients with uveitis irAEs can use periocular, topical, or systemic corticosteroids to control inflammation, and intravitreal corticosteroids can be used for treating macular edema.Some severe cases particularly require the cessation of ICI therapy.

5．藥敏紙片試驗(yàn)結(jié)果見表2。藥敏紙片試驗(yàn)結(jié)果表明敏感的藥物依次是：頭孢菌素、環(huán)丙沙星；中度敏感的依次是：青霉素和卡那霉素；而對土霉素、鏈霉素、慶大霉素具有抗藥性。

There is a lack of data for comparing the incidence, pattern,and occurrence time of uveitis induced by CTLA-4 with PD-1/PD-L1 inhibitors. Uveitis irAEs can occur in approximately 1% of patients and manifest as anterior-, posterior-, or pan-uveitis. The time to onset after the initial infusion of ICIs ranges broadly from approximately 2wk to 14mo (median time is 9wk). A typical initial chief complaint is conjunctival redness or bilateral blurred vision. Other symptoms, such as eye pain, photophobia, and floaters are also observed with uveitis. Nevertheless, the mechanisms of uveitis irAEs have yet to be assessed comprehensively.

A significant reduction in the visual acuity associated with a nonpainful redness in both eyes was found in ophthalmologic evaluation. Slit-lamp examination revealed the presence of anterior chamber cells of strong positive, bilateral granulomatous keratic precipitates, bilateral anterior, and posterior synechiae and some pigmentary deposits on the anterior lens capsule that were predominant in the left eye.Fluorescein angiography confirmed unilateral or bilateral papilledema. A light macular edema associated with a subfoveal serous retinal detachment can be revealedOCT.

Thyroid-like orbitopathy, characterized by ophthalmoplegia due to extraocular muscle involvement and proptosis, may occur in patients treated with ipilimumab even in the absence of thyroid dysfunction. It has been suggested that anti-CTLA-4 agents enhance the activation and proliferation of CD8+ T lymphocytes, facilitating the development of Grave's orbitopathy. Anti-CTLA-4 in combination with an anti-PD-L1 inhibitor has also shown to be related to Grave's orbitopathy and an inflammatory myopathy of the diplopia,extraocular muscles, ptosis, and weakness. Moreover,inflammatory orbitopathy, orbital inflammatory syndromes,and orbital apex syndrome have been described in several studies. Systemic corticosteroids can be used to manage these patients.

繁華一瓢飲止：《金粉世家》號稱民國紅樓，的確是有點(diǎn)紅樓的影子。尤其是對女性的塑造都極用心，為整部小說的基調(diào)和氛圍都增色許多。

Retinal vasculitis resulting in blurry vision secondary to pembrolizumab has been reported in the setting of metastatic cutaneous melanoma to the vitreous cavity. One patient complained of blurred vision and was treated with prednisolone eye drops. Pembrolizumab was continued, and the tumor lesion achieved complete response after 15 cycles of treatment. The ocular presentation improved after external beam radiotherapy and vitrectomy for the vitreous metastases.

Uveal effusion has been reported in patients treated with anti-PD-1/PD-L1 agents, such as pembrolizumab, nivolumab, and atezolizumab. ICI-associated uveal diffusion usually manifests as symptoms, such as redness, blurry vision, ocular, and serous choroidal detachment including the foveal presence of intraretinal and subretinal fluid. Although the uveal effusion can also be attributed to intraocular inflammation, ICI-related uveal effusion can resolve after discontinuing the immunotherapy, indicating that ICIs play an important role in causing uveal effusions.

There are isolated reports of serous retinal detachment with or without choroidopathy, immune retinopathy, exudative retinal detachment with ciliochoroidal effusion, and melanoma-associated retinopathy with atypical chorioretinal lesionsleading to photophobia and blurry vision that have been treated with variable therapies, including topical and oral corticosteroids, discontinuation of ICIs, or observation alone. Early cessation of checkpoint inhibitors has favorable visual acuity outcomes.

Conjunctivitis in patients treated by ICIs is rarely reported, and the incidence and time to onset varies by patient. In one case study, the patient complained of irritated red eyes without the impairment of vision after 13 doses of nivolumab. Conjunctiva swab test was negative,and symptoms were not relieved after antibiotic ocular drop treatment. The ophthalmologist's examination revealed bilateral sterile conjunctivitis with no signs of retinal or uveitis lesions. The manifestation was partially improved after topical steroid therapy. Two cases of conjunctivitis have been reported in a retrospective study, presenting with irritation and conjunctival injection; however, neither required ICI discontinuation. One case improved after treatment with topical corticosteroids.

Ocular myositis was reported in a case with metastatic renal carcinoma. Symptoms such as a subacute presentation of bilateral eyelid ptosis and painless ophthalmoplegia were observed after the second infusion of pembrolizumab. A mild elevation of TSH and CK was found in laboratory tests. A physical examination indicated complete, non-fluctuating, external ophthalmoplegia with bilateral eyelid ptosis. Deltoid muscle biopsy demonstrated mixed macrophagic/lymphocytic endomysial inflammatory infiltration, with prevalent CD68 and CD8 cells, sometimes expressing PD-1/PD-L1 antigens.94 MHC-I overexpression in the cytoplasm and sarcolemma was observed in nonnecrotic cell clusters. In perifascicular regions, CD56+ cells were also observed. After starting corticosteroid therapy and discontinuing pembrolizumab, the patient's symptoms were relieved and the laboratory tests normalized.

從城市土地利用集約程度的角度出發(fā)，設(shè)計(jì)各種情景仿真方案的土地利用面積變化率水平，且設(shè)定某類用地面積變化率以其用地轉(zhuǎn)入率和轉(zhuǎn)出率之差為準(zhǔn)。情景方案設(shè)計(jì)結(jié)果如表1所示，基準(zhǔn)利用方案以SD模型初始模擬結(jié)果為主，其余兩種情景模擬方案的參數(shù)值增減量均是以基準(zhǔn)利用方案相關(guān)用地面積變量值和《城鄉(xiāng)用地分類與規(guī)劃建設(shè)用地標(biāo)準(zhǔn)》（GB50137-2011）中各種人均用地量指標(biāo)為參照標(biāo)準(zhǔn)進(jìn)行。

Neuro-ophthalmic adverse events were first reported in a pediatric patient with grade 4 glioblastoma multiforme in 2018. It has also been shown to be associated with ipilimumab, but the incidence is very low. Several cases with neurologic adverse events, including optic neuritis,Grave's orbitopathy, papillitis, and myasthenia gravis have been reported to occur at a median onset of 35d after ICI therapy. Papilledema, multiple cranial neuropathies,and cerebellar ataxia with associated nystagmus have also been observed. The manifestations of neuro-ophthalmic adverse events range from mild to severe and present with visual disturbances, including part or full-field vision loss,disc edema, or scotomas. Prompt recognition, treatment,and management are crucial to prevent morbidity. Most symptoms can be alleviated with corticosteroids, but some severe optic neuropathy requires intravenous immunoglobulin or plasmapheresis. Of note, severe ophthalmoplegia induced by immunotherapy requires early intervention and treatment because of potentially fatal side events.

The granulomatous inflammation of lacrimal glands has been rarely reported. The pathogenesis of granulomatous infiltration in the context of ICIs may be attributed to IL-2 secretion by activated T cells and lymphocytic infiltration with CD8+ T cells. One patient with simultaneous and bilateral keratitis and uveitis in the setting of nivolumab therapy for metastatic melanoma was presented in a case report. The patient presented with bilateral blurred vision after the third dose of nivolumab. Other keratitis types mainly present with corneal haze and pain and can be managed with topical corticosteroids. Episcleritis induced by ipilimumab was also reported in clinical trials; however, details on therapy and outcomes were not given.

DIAGNOSING IMMUNE CHECKPOINT INHIBITORASSOCIATED OPHTHALMIC TOXICITY

Patients with ophthalmic irAEs require thorough ophthalmologic tests that can assess the presence of ophthalmologic, fundus,neurologic, and systemic disease (Figure 3). Ophthalmic evaluation is the most common form of diagnosis; nearly all patients with ICI-associated ophthalmic toxicity were identified in this manner(Figure 3). Patients with ICIrelated ophthalmic toxicity accompanying with fever and flulike symptoms were recommended treatment with antinuclear antibody during the periods of adverse events. Of note,antinuclear antibody usually has good sensitivity but poor specificity for autoimmune disease. The antinuclear antibody evaluation, either using absolute values or changes from baseline, is required to better understand the diagnostic and predictive value in cases with ocular immune-associated adverse reactions.

黨的十八大提出，建設(shè)“學(xué)習(xí)型、服務(wù)型、創(chuàng)新型馬克思主義執(zhí)政黨，確保黨始終成為中國特色社會主義事業(yè)堅(jiān)強(qiáng)領(lǐng)導(dǎo)核心”?！叭汀秉h建目標(biāo)的提出，無論從中國社會轉(zhuǎn)型時期的現(xiàn)實(shí)需要來看，還是從馬克思主義政黨觀來看，都是具有重大意義的黨建目標(biāo)定位［2］。我黨不只是當(dāng)代中國的執(zhí)政黨，更是社會的建設(shè)黨，必須讓廣大黨員干部明白黨的實(shí)質(zhì)與黨群的血肉關(guān)系，才能讓我黨成為“三型”馬克思主義政黨。

The examination of neuro-ophthalmic events may be accompanied by a series of imaging studies and ancillary laboratories based on medical history and examination findings, including infectious and autoimmune serologies,MRI, optical coherence tomography (OCT), and cerebrospinal fluid (CSF) examination. Orbital and cerebral MRI may provide ophthalmologist with valuable diagnostic and prognostic information.

ICI-associated inflammatory orbitopathy is an orbital adverse effect that presents with proptosis, pain, eyelid edema,chemosis, and extraocular motility restriction. One case of orbital myopathy that involved the extraocular muscles was associated with blepharoptosis and dyspnea and required tremelimumab and durvalumab discontinuation and the use of systemic corticosteroids.

A wide spectrum of ocular manifestations should be included in the differential diagnosis by ophthalmologists to prevent irreversible vision loss and mortality. It is worth mentioning that melanoma-associated retinopathy, a rare autoimmune disease, has been shown to be associated with the diagnosis of cutaneous melanoma. It is characterized by various optic disc findings and the presence of antiretinal antibodies. Melanoma-associated retinopathy presents with several forms of chronic visual impairments, which usually develop several months after the diagnosis of melanoma.Melanoma-associated retinopathy occurs with the melanoma diagnosis, regardless of the therapy, and is therefore easily distinguished from ICI-associated ocular toxicity.

TREATMENT AND OUTCOME OF ICI-ASSOCIATED OPHTHALMIC ENVENTS

The treatment regimens for ophthalmic irAEs vary depending on the case. Recently, detailed recommendations for the treatment of ICI-induced ophthalmic adverse events have been proposed. For patients with moderate adverse events (CTCAE grade 2, such as those involving the anterior segment), ICIs should be suspended until the symptoms reduce to grade 1 or normalize; corticosteroids may be administered. For patients with severe adverse events (grade 3 or 4, such as those involving the posterior segment), systemic corticosteroids should be administered. Large doses and long periods of corticosteroids should be avoided because of multiple adverse events that result from it.

In addition to being considered as a drug-associated toxicity,some ophthalmic toxicities, such as uveitis, may serve as a prognostic marker of response to ICIs. Attiareported a series of 56 metastatic melanoma patients treated with ipilimumab and found that autoimmunity correlated with the regression of tumor. Among those with severe irAEs, 36% had objective tumor regression compared with 5% of those without irAEs. There was also a report in which one patient developed severe ophthalmic adverse event during treatment with ipilimumab; however, the patient sustained tumor remission.Of the 15 reviewed cases, tumor regression upon manifestation of uveitis was described in 7 cases in which either a complete or partial response was obtained. There was a report of a case who was treated with pembrolizumab and soon developed symptoms, including blurred vision, hearing loss, and acute onset ataxia. Simultaneously, a robust regression of metastases was also detected. Some severe adverse events of panuveitis, such as a VVKH syndrome induced by ipilimumab,requiring high-dose oral corticosteroids have also been reported. The sequential administration of nivolumabassociated VKH disease has been reported with a positive clinical outcome.

The above evidence suggested that ICI-associated ophthalmic toxicity may be a potential marker for tumor response. As a result, the administration of corticosteroids requires careful consideration, because of possible compromise of antitumor activities of ICIs. Of note, some patients can also achieve a significant reduction of tumor burden through the symptomatic treatment for ocular adverse effects.

POSSIBLE MANAGEMENT OF OPHTHALMIC ENVENTS AND FUTURE DIRECTIONS

Effective communication with a multidisciplinary team and primary care provider is essential for the prompt recognition and management of ICI-related ophthalmic events. In the era of anticancer immunotherapies, first, it is of great importance for clinicians to distinguish ICI-related events from potential autoimmune-associated causes and common toxic adverse events. Second, it is vital that ophthalmologists do not mistake uveitis-like manifestations as purely inflammatory. The eye is an immune-privileged organ; even in the setting of an otherwise complete systemic response to therapy, it may be vulnerable to metastases. Two published case reports described cutaneous melanoma metastatic to the vitreous cavity and retina in patients treated with ICIs. These studies elucidated how such manifestations can be confused with inflammatory uveitis but require different management and may have an important impact on prognosis. Third, in the context of a diagnostic dilemma, eliciting a history of systemic irAEs and understanding ophthalmic irAEs that are rarely isolated are critical.

In general, most ophthalmic toxicities can initially be managed by periocular, topical, or systemic corticosteroids. In practice,when the ocular inflammation is mild or only covers the anterior segment, ICI discontinuation might not be required.Of course, the evaluation for the cessation or discontinuation of treatment will vary on a case-by-case basis depending on the severity and availability of ophthalmologic treatment. In severe or steroid-refractory cases, in which the symptoms are debilitating, it is necessary for ophthalmologists to consult with oncologists in determining the benefits and risk of cessation or continuation of ICIs. Immunotherapy discontinuation resulting in the spontaneous resolution of symptoms has rarely been reported. Steroids are required for most patients to alleviate the duration and intensity of symptoms.Alternative immunomodulatory therapies, such as intravenous immunoglobulin or plasma exchange, may offer additional benefits for patients with severe ophthalmologic events.

李劼人筆下的女性雖然獨(dú)立自主，在那個仍然封建落后的社會環(huán)境下和三從四德的傳統(tǒng)女性相比具有超前性和先鋒性，但是她們?nèi)匀辉谀袡?quán)主義下苦苦掙扎生存。他們并沒有完全擺脫男性的壓迫和摧殘，她們雖然有一定的獨(dú)立自主意識，但是她們?nèi)匀粩[脫男性而獨(dú)立生存。她們渴望浮出水面，卻只能在呼吸和窒息中掙扎。

It is controversial whether ICIs should be re-introduced after recovery from ophthalmic toxicity. Although ophthalmic dysfunction can be significantly improved by corticosteroid therapy, an anti-PD1 agent re-challenge might induce symptom recurrence and even aggravate immune-related toxicities. In particular, the re-challenge of ICIs after a grade 3 toxicity requires extreme precaution. These recommendations may include some specific genres, such as uveitis, episcleritis, and blepharitis, but do not address other possible ocular presentations. It is important to be aware of the recurrence of adverse events after the re-introduction of ICIs. The management of the recurrence of ophthalmic toxicity is also challenging. As a result, the collaboration of clinical oncologists and ophthalmologists should give careful consideration to patients according to their presentations,outcomes, and alternative cancer therapy options to weigh the pros and cons of reintroducing immunotherapy.

隨著我國加入WTO，中國將會成為世界煙葉生產(chǎn)和消費(fèi)的中心，但是我國煙葉的生產(chǎn)和質(zhì)量水平與世界煙草大國相比還有相當(dāng)大的差距。煙葉生產(chǎn)環(huán)節(jié)多，技術(shù)要求高，煙農(nóng)零星分散種植，不利于生產(chǎn)水平和煙葉質(zhì)量的提高。美國、巴西、津巴布韋等煙葉生產(chǎn)大國早在20世紀(jì)90年代末就全部采取了農(nóng)場化種植、機(jī)械化操作、企業(yè)化管理的經(jīng)營模式，煙葉生產(chǎn)的各環(huán)節(jié)都采取了機(jī)械化作業(yè)的模式，降低了生產(chǎn)成本，提高了烤煙生產(chǎn)的科技含量，煙葉產(chǎn)量、質(zhì)量和效益較好，市場競爭力強(qiáng)。目前，發(fā)展適度規(guī)模種植，進(jìn)行機(jī)械化作業(yè)、規(guī)范化管理已經(jīng)成為烤煙生產(chǎn)適應(yīng)國內(nèi)、國際市場形勢，提高生產(chǎn)水平和煙葉質(zhì)量的發(fā)展方向。

CONCLUSION

ICIs, either alone or in combination with other therapies, can lead to ophthalmic adverse reactions, such as dry eyes, uveitis,ocular myasthenia gravis, uveal effusion, retinal detachment,conjunctivitis, ocular myositis, vasculitis, keratitis, episcleritis,and a wide spectrum of neuro-ophthalmic toxicities. Of all ICI-related ophthalmic events, dry eyes and uveitis are the most common ophthalmic adverse reactions. Although the incidence of ophthalmic toxicities induced by ICIs remains relatively low, oncologists and ophthalmologists must be vigilant for these adverse reactions because permanent damage and blindness can result from neglect. The time to onset and clinical presentations of ophthalmic irAEs are variable. They can occur at any time during treatment, including after the cessation of ICIs with nonspecific symptoms ranging from blurred vision, painless ophthalmoplegia, diplopia, eyelid swelling, eye redness, floaters, exophthalmos, vision loss to shaped scotoma, headaches, and auditory changes. The assessment of ophthalmic evaluation in combination with autoimmune serologies, OCT, CSF, fundus examination, slitlamp examination, fluorescein angiography, MRI, and biopsy,if necessary, contribute to the diagnosis of ICI-related ophthalmic adverse reactions. Among these diagnostic methods,ophthalmic evaluation is easily performed and has widespread availability. Before the initiation of ICIs, a comprehensive assessment of ophthalmic risk factors and a detailed ophthalmic history should be obtained, particularly for patients with autoimmune disease or pre-existing ophthalmic disease and in the context of ICIs combined with other regimens. For patients with confirmed ophthalmic events, most ophthalmic toxicities can initially be managed by periocular, topical or systemic corticosteroids. In severe or steroid-refractory cases,alternative immunomodulatory therapies, such as intravenous immunoglobulin or plasma exchange, might offer additional benefits. Ophthalmologists need to discuss with oncologists to determine the benefits and risks of discontinuing ICIs. Of note,ICI-associated ophthalmic events may be a potential positive marker for tumor response. In addition, ophthalmic function re-assessments and frequent monitoring are necessary. To better understand these events and provide effective therapy strategies, larger studies are needed.

None;None;None;None;None;None.