Predictive Performance of an Updated Polygenic Risk Score for Age-Related Macular Degeneration.

PURPOSE: A recent genome-wide association study of age-related macular degeneration (AMD) identified new AMD-associated risk variants. These variants now can be incorporated into an updated polygenic risk score (PRS). This study aimed to assess the performance of an updated PRS, PRS2023, in an independent cohort of older individuals with retinal imaging data and to compare performance with an older PRS, PRS2016. DESIGN: Cross-sectional study. PARTICIPANTS: A total of 4175 participants of European ancestry, 70 years of age or older, with genotype and retinal imaging data. METHODS: We used logistic regression models and area under the receiver operating characteristic curve (AUC) to assess the performance of PRS2023 compared with PRS2016. AMD status and severity were graded using color fundus photography. MAIN OUTCOME MEASURES: Association of PRS2023 and PRS2016 with AMD risk at baseline. RESULTS: At enrollment among 4175 participants, 2605 participants (62.4%) had no AMD and 853 participants (20.4%), 671 participants (16.1%), and 46 participants (1.1%) had early, intermediate, and late-stage AMD, respectively. More than 27% of the participants with a high PRS2023 (top quartile) had intermediate or late-stage AMD, compared with < 15% for those in the middle 2 quartiles and less than 13% for those in the lowest quartile. Both PRS2023 and PRS2016 were associated significantly with AMD after adjustment for age, sex, smoking status, and lipid levels, with increasing odds ratios (ORs) for worsening AMD grades. PRS2023 outperformed PRS2016 (P = 0.03 for all AMD and P = 0.03 for late AMD, DeLong test comparing AUC). PRS2023 was associated with late-stage AMD with an adjusted OR of 5.05 (95% confidence interval [CI], 3.41-7.47) per standard deviation. The AUC of a model containing conventional or nongenetic risk factors and PRS2023 was 91% (95% CI, 87%-95%) for predicting late-stage AMD, which improved 12% over the model without the PRS (AUC, 79%; P < 0.001 for difference). CONCLUSIONS: A new PRS, PRS2023, for AMD outperforms a previous PRS and predicts increasing risk for late-stage AMD (with stronger association for more severe imaging-confirmed AMD grades). Our findings have clinical implications for the improved prediction and risk stratification of AMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Tumor-targeted nanodrug FSGG/siGal-9 for transdermal photothermal immunotherapy of melanoma.

Photothermal therapy (PTT) is a cancer-targeted treatment approach.The occurrence of tumors may be related to microbial infections (Viruses, bacteria, fungi, etc.), which probably provokes anti-tumor immunity. However, T cells in the context of cancer become exhausted and dysfunctional. Galectin-9 (Gal-9) is highly expressed in normal tissues and associates with body immune tolerance, and was firstly evidenced with much higher expression on the primary solid tumors than CD80/86 (B7) and CD274 (PD-L1) here, which suggests that Gal-9 may be a key factor in inhibiting the anti-tumor immunity, and its receptor T cell immunoglobulin and mucin domain 3 (TIM-3) was discovered on the cytotoxic T lymphocytes (CTL) with high expression as well based on the single cell analysis. The immune checkpoint communications showed that the Gal-9/TIM-3 axis played the most vital role on negatively regulating the anti-tumor immunity of CTL for melanoma. Then, we used a novel transdermal photothermal nanosensitizer (FSGG) loading Gal-9 siRNA (FSGG/siGal-9) for knocking the tumor cells down Gal-9 to block the Gal-9/TIM-3 axis and prohibit CTL exhaustion synergizing PTT against melanoma, which evidenced good effects on inhibiting tumor growth and enhancing anti-tumor immunity, named "photothermal immunotherapy". This paper provides a new perspective for tumor prevention and treatment.

Study profile: the Genetics of Glaucoma Study.

PURPOSE: Glaucoma, a major cause of irreversible blindness, is a highly heritable human disease. Currently, the majority of the risk genes for glaucoma are unknown. We established the Genetics of Glaucoma Study (GOGS) to identify disease genes and improve genetic prediction of glaucoma risk and response to treatment. PARTICIPANTS: More than 5700 participants with glaucoma or a family history of glaucoma were recruited through a media campaign and the Australian Government healthcare service provider, Services Australia, making GOGS one of the largest genetic studies of glaucoma globally. The mean age of the participants was 65.30±9.36 years, and 62% were female. Participants completed a questionnaire obtaining information about their glaucoma-related medical history such as family history, glaucoma status and subtypes, surgical procedures, and prescriptions. The questionnaire also obtained information about other eye and systemic diseases. Approximately 80% of the participants provided a DNA sample and ~70% consented to data linkage to their Australian Government Medicare and Pharmaceutical Benefits Scheme schedules. FINDINGS TO DATE: 4336 GOGS participants reported that an optometrist or ophthalmologist has diagnosed them with glaucoma and 3639 participants reported having a family history of glaucoma. The vast majority of the participants (N=4393) had used at least one glaucoma-related medication; latanoprost was the most commonly prescribed drug (54% of the participants who had a glaucoma prescription). A subset of the participants reported a surgical treatment for glaucoma including a laser surgery in 2008 participants and a non-laser operation in 803 participants. Several comorbid eye and systemic diseases were also observed; the most common reports were ocular hypertension (53% of the participants), cataract (48%), hypertension (40%), nearsightedness (31%), astigmatism (22%), farsightedness (16%), diabetes (12%), sleep apnoea (11%) and migraines (10%). FUTURE PLANS: GOGS will contribute to the global gene-mapping efforts as one of the largest genetic studies for glaucoma. We will also use GOGS to develop or validate genetic risk prediction models to stratify glaucoma risk, particularly in individuals with a family history of glaucoma, and to predict clinical outcomes (eg, which medication works better for an individual and whether glaucoma surgery is required). GOGS will also help us answer various research questions about genetic overlap and causal relationships between glaucoma and its comorbidities.

[Remifentanil preconditioning lowers cardiac troponin I levels in patients undergoing off-pump coronary artery bypass graft surgery].

OBJECTIVE: To investigate the value of cardiac troponin I (cTnI) levels in assessing myocardial protection by remifentanil precondition against myocardial injury induced by off-pump coronary artery bypass (OPCAB). METHODS: Twenty-four patients undergoing OPCAB were randomized into control and remifentanil preconditioning group (n=12). All the patients received pretreatment with oral diazepam (10 mg), intramuscular morphine (10 mg) and hyosine (0.3 mg). General anesthesia was induced with midazolam (0.08 mg/kg), etomidate (0.1-0.3 mg/kg), fentanyl (5-10 microg/kg), and rocuronium (1 mg/kg), and maintained with isoflurane inhalation and propofol infusion. Intermittent fentanyl and pipecuronium were given intravenously. In remifentanil preconditioning group, remifentanil (5 microg/kg in 50 ml normal saline) was infused in 10 min after anesthesia induction, and only NS was administered in the control group. Blood samples were obtained before and at 0, 2, 6, 24, and 48 h after the operation to determine serum cTnI levels. RESULTS: In both of the two groups, the cTnI levels increased significantly at the postoperative time points (0, 2, 6, 24, and 48 h) as compared with those before the operation (P<0.05). The cTnI levels of remifentanil preconditioning group were markedly decreased after the operation in comparison with those of the control group (P<0.05). CONCLUSION: Remifentanil preconditioning decreases the cTnI levels and reduces myocardial injury induced by OPCAB.

[Effect of ulinastatin on inflammatory responses induced by oesophagectomy].

OBJECTIVE: To examine the effect of ulinastatin (UTI) on the inflammatory responses induced by oesophagectomy. METHODS: Forty patients with esophageal cancer (without serious hypertension, heart disease, or respiratory function impairment, including 34 men and 6 women aged 46 to 70 years) scheduled for oesophagectomy via left thoracotomy were randomly divided into control group (n=20) and UTI group (n=20). Anesthesia induction and perioperative management followed the same protocols in the two groups, and in UTI group, patients received 5000 U/kg UTI while those in the control group were given the same volume of saline. Before operation (T(1)), 10 min after recovery of two-lung ventilation (T(2)), and 24 h (T(3)) and 48 h (T(4)) after operation, the venous blood sample was taken from the internal jugular vein and the plasma was separated and stored at -70 degrees C for later analysis of IL-6 and IL-8 with enzyme-linked immunosorbent assay (ELISA). The bronchoalveoar lavage fluid (BAFL) was also collected at T(1) and T(2) for IL-6 and IL-8 detection. RESULTS: IL-6, IL-8 levels in the plasma and BALF collected at T(2)-T(4) increased significantly as compared with those in samples collected at T(1), and their peak concentration inplasma and BALF samples were similar. IL-6 and IL-8 levels in the UTI group were significantly lower than those in the control group during the time points of T(2)-T(4). CONCLUSION: Inflammatory responses occur during and after oesophagectomy, which can be inhibited with UTI.

Prognosis of hepatic cirrhosis patients with esophageal or gastric variceal hemorrhage: multivariate analysis.

OBJECTIVE: To study the effect of bacterial infection, use of antibiotics, active bleeding at endoscopy, and the severity of liver disease as prognostic factors in hepatic cirrhotic patients during the first 5 days after the episode of esophageal or gastric variceal hemorrhage. METHODS: Seventy-six hepatic cirrhosis patients with esophageal or gastric variceal bleeding were enrolled. Bleeding was managed in a standardized protocol using octreotide and vasopressin in sclerotherapy or band ligation for active bleeding at endoscopy. The screening protocol for bacterial infection consisted of chest radiograph; blood, urine and ascitic fluid cultures; the severity of liver disease shown by Child-Pugh score. RESULTS: Active bleeding was observed at endoscopy in 40 patients (53%). Failure to control bleeding within 5 days occurred in 36 patients (45%). Empirical antibiotic treatment was used in 53 patients (67%), whereas bacterial infections were documented in 43 patients (57%). Multivariate analysis showed that proven bacterial infection (P<0.01) or antibiotic use (P<0.05) as well as active bleeding at endoscopy (P<0.01) and Child-Pugh score (P<0.01) were independent prognostic factors of failure to control bleeding. CONCLUSION: Bacterial infection is associated with failure to control esophageal or gastric variceal bleeding in hepatic cirrhotic patients.