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ABSTRACTBackgroundCenegermin, a recombinant human nerve growth factor, is an orphan drug approved for neurotrophic keratitis. The safety information on the label is incomplete, and the adverse reactions noted are mostly mild and tolerable. However, the occurrence of painful epithelial plagues and irreversible corneal deposits after cenegermin usage have been reported. Real-world data on long-term ocular safety are lacking. We aimed to assess the cenegermin-associated eye safety profile in the FDA pharmacovigilance database.MethodsThe signals of cenegermin-related ocular adverse events (AEs) from 2018 to 2022 were quantified using the reporting odds ratio (ROR) and information component (IC). The grading system was used to prioritize the signals.ResultsWe identified 3288 cases of cenegermin-related ocular AEs and 56 positive ocular-related signals. Fifty unexpected signals of ocular AE were identified. Eye ulcer was classified as a designated medical event. Twenty AEs, including corneal perforation, eye infection, corneal deposits, and eye inflammation, were recognized as important medical event. The median onset time for ocular AEs was 6 days (interquartile range [IQR]: 1–29 days).ConclusionThis study revealed new cenegermin-related ocular AE signals. Clinical practice requires close monitoring to early identify and manage adverse reactions that may cause occurrence of serious irreversible consequences.

Objectives: To determine the clinical features and course of thyroid-associated ophthalmopathy (TAO) in a large sample of Chinese patients. Design and methods: We retrospectively identified a cohort of consecutive patients diagnosed with TAO at the West China Hospital from October 1, 2009 to October 1, 2019. We analysed clinical data from 3620 patients, including demographic data, clinical manifestations, ophthalmology examinations, and prognosis. Results: TAO most frequently occurred with hyperthyroidism, with most patients developing TAO after thyroid disease (TD). The TAO phenotype was asymmetric in 375 (50.7%) euthyroid patients, 25 (27.8%) hypothyroid patients, and 314 (12.1%) hyperthyroid patients (p< 0.0001). The most frequent symptom was lid lag and the most commonly involved extraocular muscle was the inferior rectus. Severity assessment (NOSPECS score) and clinical activity assessment (Clinical Activity Scores, CAS) differed significantly between male and female patients (P< 0.000). The majority (88.8%) of patients had clinically inactive TAO, and only 3.2% of cases were sight-threatening. Regarding the clinical process, 75.5% of patients had an active phase time less than 12 months and 2.1% showed complete remission. Conclusions: TAO most commonly develops in females and is closely related to hyperthyroidism. Euthyroid TAO often has an asymmetric clinical phenotype. CAS combined with magnetic resonance imaging can improve the detection of TAO. NOSPECS scores should be slightly refined regarding the criteria for corneal involvement. Clinical management of TAO should be individualized according to CAS or NOSPECS assessments and a multidisciplinary approach is paramount. A minority of patients showed complete remission.

Improved resolution of molecular diagnostic technologies enabled detection of smaller sized exonic level copy-number variants (CNVs). The contribution of CNVs to autosomal recessive (AR) conditions may be better recognized using a large clinical cohort.

Fungal orbital cellulitis is usually seen in immunocompromised individuals, and opportunistic pathogens are the main etiology. We herein report a case of fungal orbital cellulitis due to Aspergillusin a patient with no history of trauma. A 48-year-old man presented to the emergency room of our hospital with a 2-week history of periorbital swelling, conjunctival hyperemia, and chemosis of his right eye. The visual acuity of his right eye was 6/20, and the intraocular pressure was 44 mmHg. The main clinical findings were proptosis of the right ocular globe with conjunctival hyperemia and a palpable infratemporal orbital mass. Laboratory testing failed to detect the presence of a pathogenic infection, and the lesions on computed tomography images resembled those of a malignant tumor of the orbit. The diagnosis was finally confirmed by postoperative pathological examination, and the patient responded favorably to debridement combined with antifungal therapy. Histopathological examination may help to reveal the nature of this disease. Surgical removal of inflammatory lesions can serve as an important diagnostic and treatment method for fungal orbital cellulitis.

Synthesis of 2‐amino‐3‐perfluoroalkylfurans has been accomplished by isocyanide‐based multicomponent reactions. Using methyl perfluoroalk‐2‐ynoates as the fluorinated build blocks in combination with isocyanides and aromatic aldehydes in one‐pot at room temperature, the perfluoroalkyl‐substituted 2‐aminofurans were obtained in good to excellent yields. MCRs: 2‐Amino‐3‐perfluoroalkylfurans were synthesized in good to excellent yields by catalyst‐free one‐pot multicomponent reactions of isocyanides, methyl perfluoroalk‐2‐ynoates and aromatic aldehydes at room temperature.

The first efficient intermolecular reaction of gold carbene intermediates generated via gold-catalyzed alkyne oxidation has been realized using nitriles as both the reacting partner and the reaction solvent, offering a generally efficient synthesis of 2,5-disubstituted oxazoles with broad substrate scope. The overall reaction is a [2 + 2 + 1] annulation of a terminal alkyne, a nitrile, and an oxygen atom from an oxidant. The reaction conditions are exceptionally mild, and a range of functional groups are easily tolerated. With complex and/or expensive nitriles, only 3 equiv could be sufficient to achieve serviceable yields in the absence of any solvent and using only 1 mol % BrettPhosAuNTf2as the catalyst.

Polyoxymethylene methacrylate (PMMA) is widely used in ophthalmic biomaterials. Misuse of PMMA in extreme environments is likely to damage the ocular surface and intraocular structures. The surface characterization and tribological behavior of PMMA processed using an excimer laser were investigated in this study by contrasting different lubrication conditions and friction cycles. The results show that the roughness of the material surface increases with laser processing, which changes its physical structure. Under lubrication, the laser-treated PMMA exhibits better hydrophilicity, especially during the use of eye drops. No obvious relationship exists between the laser-processing time and friction behavior. However, the laser treatment may contribute to the formation of friction and wear mechanisms of PMMA materials. Laser-treated PMMA in saline solution exhibits better abrasive resistance by showing a lower wear rate than that in eye drops, although it has a higher friction coefficient. In this study, the different friction stages in laser-treated PMMA were clarified under two lubrication conditions. The wear rates of the laser-treated PMMA were found to decrease with the number of cycles, and the friction coefficient has a similar variation tendency. The wear behavior of the laser-treated PMMA is dominated by the main abrasive wear and secondary transferred film formation. This study provides a theoretical basis for the development and application of ophthalmic biomaterials in complex environments by examining the material surface interface behavior and wear mechanism after laser processing using PMMA as the research matrix.

Fluoroalkylated quinoxlines with various groups were efficiently synthesized via a one-pot tandem Michael addition/azidation/cycloamination process. Under the mild and metal-free conditions, a bis-imine intermediate (4a) was detected and isolated for the first time. KI played a crucial role in this reaction. The mechanism was described.

There are limited data on what is the minimum change that can be detected in cancer patients undergoing treatment with cardiotoxic drugs and are referred for monitoring left ventricular (LV) function.To assess the variability in the measurement of LV volumes and ejection fraction (EF) in contrast echocardiography and to determine the minimum detectable difference (MDD) between two EF measurements that can be deemed significant.A total of 150 patients were divided into three groups according to EF (EF <53, 53–60, and >60%). Each group consisted of 50 randomly selected cancer patients who underwent contrast echocardiography between July 2010 and May 2014. Repeated measurements of LV volumes and EF were performed offline by a sonographer and a cardiologist. Inter-observer variability was assessed by analysis of variance. Measurement error was estimated by standard error of measurement and MDD.The 95% confidence interval with a single measurement of EF was 2 percentage points in the groups of patients with EF <53% and EF >60%, and 2.5 percentage points for patients with EF 53–60%. The MDD for EF, end-diastolic volume and end-systolic volume that could be recognized with 95% confidence interval were 4 percentage points, 7 mL and 4 mL, respectively.Contrast echocardiography is a reliable tool for serial measurements of EF to monitor cardiotoxicity due to chemotherapy. In a high-volume echocardiography laboratory with experienced staff, the MDD for EF of 4 percentage points on a good-quality recording demonstrates the high reproducibility of the Simpson’s method using contrast echocardiography.

Neuroendocrine neoplasms (NENs) originate from neuroendocrine cells, and mainly occur in the gastrointestinal tract and lungs, rarely occurring in the orbit. Here, the clinicopathologic factors, treatments and prognosis of three cases of orbital NENs are described. The mean age of the three patients (two females and one male) was 59 years. Two cases exhibited ocular symptoms, including unilateral proptosis and eyelid mass, while the third case presented systemic symptoms exhibited as Cushing’s syndrome. The tumours were surgically resected in all three patients. Immunohistochemistry assays revealed positive expression for pan cytokeratin and epithelial membrane antigen in all cases. Additionally, neural cell adhesion molecule 1 (also known as CD56) and synaptophysin were positive in two cases. The pathological diagnosis for case 1 and 2 was ‘neuroendocrine carcinoma’ and both patients died three months after diagnosis. Case 3 was diagnosed with a neuroendocrine tumour and the symptoms of Cushing’s syndrome gradually improved following surgery. In addition, no recurrence was observed during the four-year follow-up period. These cases demonstrate that orbital neuroendocrine tumours show different clinical manifestations due to the different types. Pathology may clarify the diagnosis, classification and grading, and provide a reference value for treatment and prognosis.

Whole-exome sequencing can identify variations in an individual’s DNA sequence and compare them with a normal reference sequence, a process that can help to determine the cause of a patient’s medical disorder. Although results of prior studies on clinical applications of these techniques have been promising, many questions remain unanswered. This study was undertaken to determine clinical findings of whole-exome sequencing in 2000 consecutive patients.

Chiral rings made easy: Chiral azetidin‐3‐ones have been easily prepared from chiral N‐propargylsulfonamides, which in turn are readily accessible through chiral sulfinamide chemistry (see scheme). Using tert‐butylsulfonyl as the protecting group avoids unnecessary deprotection and reprotection steps, and allows its removal from the azetidine ring under acidic conditions.

So kommt man zu chiralen Ringen: Chirale Azetidin‐3‐one waren einfach aus chiralen N‐Propargylsulfonamiden erhältlich, die wiederum leicht über chirale Sulfinamide zugänglich sind (siehe Schema). Die tert‐Butylsulfonyl‐Schutzgruppe machte weitere Schützungs‐ und Entschützungsschritte unnötig und ließ sich unter sauren Bedingungen vom Azetidinring abspalten.

To maintain cost competitiveness for the 200 mm wafer production, the industry starts to explore production feasibility under groundrules smaller than 110 nm while maintaining the cost advantages given by the KrF exposure tools systems. The k1 factor under 110 nm will be below 0.35. It has the similar level of complexity in optical proximity correction compared to 65 nm at 0.93 NA with 193 nm exposure tools. However, due to that the KrF photoresists are originally designed for ground rules greater than 110 nm it is relatively unknown how feasible it is to extend their performance below 110 nm. As we know, in each photoresist design, there is a balance among three major performance indices, which are spatial resolution, photospeed, and pattern edge roughness. For example, a fast photoresist may not have the same resolution or pattern edge roughness performance as a slow photoresist, which may, of course, has low productivity. A good production resist usually has a good balance of all three parameters. This paper will explore the line edge roughness parameters under sub 110 nm design rules and will explore the performance dependence on imaging conditions. Classical photo process optimization result is shown and acceptable LWR performance is achieved. In addition, a comparison in line edge roughness among 3 production KrF photoresists will be made.

Amid continuing reduction in average wafer sale price, in the past 30 years, the industry witnesses continuous shrink in production design rules in order to gain performance per unit area on each silicon wafer. While the mainstream wafer production is at 65 and 45 nm with 300 mm diameter wafers, to maintain cost competitiveness, 200 mm wafer companies also start to explore production feasibility under groundrules smaller than 110 nm while maintain the cost advantages in KrF exposure tools systems. The k1 factor under 110 nm with 248 nm illumination will be below 0.35. For example, at 90 nm, at 0.80 NA, the k1 factor is 0.29, which owns the same level of complexity in optical proximity correction compared to 65 nm at 0.93 NA with 193 nm exposure tools. However, due to that the KrF photoresists are originally designed for ground rules greater than 110 nm, such as, 130 nm structures, it is relatively unknown how feasible it is to extend their performance below 110 nm. In this paper, we will show our initial study in CD process window and CD through pitch performance at 90 nm groundrule for 3 critical layers - Active, Gate poly and Contact. The wafer data in process window and optical proximity will be analyzed and compared with performance specifications of the current exposure tools.

Lymphoma is common in IgG4-related disease, but diffuse large B-cell lymphoma in IgG4-related ophthalmic disease is rare, especially involving the same organ affected by IgG4-related ophthalmic disease. The authors report a 44-year-old man presented with bilateral proptosis for 10 years and rapid loss of vision in the right eye for the last 1 month. The authors performed orbital exenteration for the right eye and resected the tumor in the left eye. Based on the clinicopathologic findings, tumors of the right and left eyes were diagnosed as diffuse large B-cell lymphoma and IgG4-related ophthalmic disease, respectively. This case highlights the risk of malignant transformation of IgG4-related ophthalmic disease.The authors report a rare case that diffuse large B-cell lymphoma combining with IgG4-related ophthalmic disease occurred at the same site of the homolateral orbit.

Insulin receptor substrate 1 (IRS-1) and srchomology and collagen protein (SHC) are signaling proteins which are rapidly phosphorylated on tyrosines after insulin receptor (IR) activation. We have recently shown that both SHC and IRS-1 interact with the tyrosine-phosphorylated NPEY motif of the IR and insulin-like growth factor I receptor via non-SH2 domains (Gustafson, T. A., He, W., Craparo, A., Schaub, C. D., and O'Neill, T. J.(1995) Mol. Cell. Biol.15, 2500-2508; O'Neill, T. J., Craparo, A., and Gustafson, T. A.(1994) Mol. Cell. Biol.14, 6433-6442; Craparo, A., O'Neill, T. J., and Gustafson, T. A.(1995) J. Biol. Chem.270, 15639-15643). In this study we characterize these interactions by examining the effects of 18 amino acid substitutions within and around the IR NPEY motif upon interaction with SHC and IRS-1. We confirm that Tyr-960 within the NPEY motif of the IR is essential for both IRS-1 and SHC interaction and that Asn-957 and Pro-958 are essential for IRS-1 interaction and important but not critical for SHC interaction. Additional mutations surrounding the NPEY motif revealed completely distinct patterns of interaction for SHC and IRS-1. Specifically, mutation of Leu-952 or Tyr-953 (at positions −7 and −8 from Tyr-960) markedly reduced IRS-1 interaction but had no effect upon SHC interaction. Likewise, mutation of Ala-963 (+3) reduced IRS-1 but not SHC interaction. Conversely, substitution of Leu-961 (+1) with either Ala or Arg reduced SHC interaction by 70 and 90%, respectively, yet had no effect upon interaction with IRS-1. Our data show that the sequences within and surrounding the NPEY contribute differentially to either SHC or IRS-1 recognition. Our findings suggest mechanisms by which the differential interaction of known receptors with IRS-1 and SHC may be mediated.

Insulin receptor substrate 2 (IRS-2) has recently been shown to be a substrate of the insulin receptor (IR). In this study we utilize the yeast two-hybrid system and assays of in vitrointeraction to demonstrate that IRS-2 interacts directly with the IR and the insulin-like growth factor I receptor. We show that, like IRS-1, the region of IRS-2 that contains the putative phosphotyrosine binding and SAIN elements(188-591) is sufficient for receptor interaction and that this interaction is dependent upon the NPX(p)Y (where (p)Y is phosphotyrosine) motifs within the juxtamembrane domains of the receptors. In addition to this amino-terminal NPX(p)Y-binding domain, an additional domain of strong interaction was identified in the central region of IRS-2 and was localized between amino acids 591 and 733. This interaction was found to be dependent upon receptor phosphorylation but was NPX(p)Y-independent. This region does not appear to have either an SH2 or a phosphotyrosine binding domain. Both of the interactions could also be demonstrated in vitrousing IRS-2 glutathione S-transferase fusion proteins. We conclude that IRS-2, unlike IRS-1, can interact with tyrosine-phosphorylated receptors such as the IR and insulin-like growth factor I receptor via multiple independent binding motifs. Our findings suggest the existence of a previously unidentified phosphotyrosine-dependent binding domain within the central region of IRS-2.

IMPORTANCE: While congenital malformations and genetic diseases are a leading cause of early infant death, to our knowledge, the contribution of single-gene disorders in this group is undetermined. OBJECTIVE: To determine the diagnostic yield and use of clinical exome sequencing in critically ill infants. DESIGN, SETTING, AND PARTICIPANTS: Clinical exome sequencing was performed for 278 unrelated infants within the first 100 days of life who were admitted to Texas Children’s Hospital in Houston, Texas, during a 5-year period between December 2011 and January 2017. Exome sequencing types included proband exome, trio exome, and critical trio exome, a rapid genomic assay for seriously ill infants. MAIN OUTCOMES AND MEASURES: Indications for testing, diagnostic yield of clinical exome sequencing, turnaround time, molecular findings, patient age at diagnosis, and effect on medical management among a group of critically ill infants who were suspected to have genetic disorders. RESULTS: The mean (SEM) age for infants participating in the study was 28.5 (1.7) days; of these, the mean (SEM) age was 29.0 (2.2) days for infants undergoing proband exome sequencing, 31.5 (3.9) days for trio exome, and 22.7 (3.9) days for critical trio exome. Clinical indications for exome sequencing included a range of medical concerns. Overall, a molecular diagnosis was achieved in 102 infants (36.7%) by clinical exome sequencing, with relatively low yield for cardiovascular abnormalities. The diagnosis affected medical management for 53 infants (52.0%) and had a substantial effect on informed redirection of care, initiation of new subspecialist care, medication/dietary modifications, and furthering life-saving procedures in select patients. Critical trio exome sequencing revealed a molecular diagnosis in 32 of 63 infants (50.8%) at a mean (SEM) of 33.1 (5.6) days of life with a mean (SEM) turnaround time of 13.0 (0.4) days. Clinical care was altered by the diagnosis in 23 of 32 patients (71.9%). The diagnostic yield, patient age at diagnosis, and medical effect in the group that underwent critical trio exome sequencing were significantly different compared with the group who underwent regular exome testing. For deceased infants (n = 81), genetic disorders were molecularly diagnosed in 39 (48.1%) by exome sequencing, with implications for recurrence risk counseling. CONCLUSIONS AND RELEVANCE: Exome sequencing is a powerful tool for the diagnostic evaluation of critically ill infants with suspected monogenic disorders in the neonatal and pediatric intensive care units and its use has a notable effect on clinical decision making.

A variety of terminal alkynes were converted into the corresponding 4-(2-oxoalkoxy)butyl methanesulfonates via a gold-catalyzed intermolecular oxidation reaction using 8-ethylquinoline N-oxide as the oxidant and THF as the solvent. This reaction is proposed to proceed through the ring-opening of THF via an α-oxo gold carbene intermediate.

A new one-pot method for synthesis of homopropargylic N-sulfonylamines from aldehydes catalyzed by zinc powder is described. The procedure is lauded by its simplicity, good yields, and adaptability to a wide variety of aldehydes.

Gold‐catalyzed alkyne oxidation generates gold carbene intermediates which smoothly react with nitriles to give title disubstituted oxazoles, e.g. (III), (V), (VII) or (X), in good yields.

A practical synthesis of azetidin‐3‐ones including chiral derivatives is developed through gold‐catalyzed oxidative cyclization of N‐propargylsulfonamides.

This strategy uses alkynes as synthetic equivalents to α—diazoketones for accessing intermediary α—oxo metal carbenes.

Amid continuing reduction in average wafer sale price, in the past 30 years, the industry witnesses continuous shrink in production design rules in order to gain performance per unit area on each silicon wafer. While the mainstream wafer production is at 65 and 45 nm with 300 mm diameter wafers, to maintain cost competitiveness, 200 mm wafer companies also start to explore production feasibility under groundrules smaller than 110 nm while maintain the cost advantages in KrF exposure tools systems. The k1 factor under 110 nm with 248 nm illumination will be below 0.35. For example, at 90 nm, at 0.80 NA, the k1 factor is 0.29, which owns the same level of complexity in optical proximity correction compared to 65 nm at 0.93 NA with 193 nm exposure tools. However, due to that the KrF photoresists are originally designed for ground rules greater than 110 nm, such as, 130 nm structures, it is relatively unknown how feasible it is to extend their performance below 110 nm. In this paper, we will show our initial study in CD process window and CD through pitch performance at 90 nm groundrule for 3 critical layers - Active, Gate poly and Contact. The wafer data in process window and optical proximity will be analyzed and compared with performance specifications of the current exposure tools.

To maintain cost competitiveness for the 200 mm wafer production, the industry starts to explore production feasibility under groundrules smaller than 110 nm while maintaining the cost advantages given by the KrF exposure tools systems. The k1 factor under 110 nm will be below 0.35. It has the similar level of complexity in optical proximity correction compared to 65 nm at 0.93 NA with 193 nm exposure tools. However, due to that the KrF photoresists are originally designed for ground rules greater than 110 nm it is relatively unknown how feasible it is to extend their performance below 110 nm. As we know, in each photoresist design, there is a balance among three major performance indices, which are spatial resolution, photospeed, and pattern edge roughness. For example, a fast photoresist may not have the same resolution or pattern edge roughness performance as a slow photoresist, which may, of course, has low productivity. A good production resist usually has a good balance of all three parameters. This paper will explore the line edge roughness parameters under sub 110 nm design rules and will explore the performance dependence on imaging conditions. Classical photo process optimization result is shown and acceptable LWR performance is achieved. In addition, a comparison in line edge roughness among 3 production KrF photoresists will be made.