Click Chemistry Selectively Activates an Auristatin Protodrug with either Intratumoral or Systemic Tumor-Targeting Agents.

The Click Activated Protodrugs Against Cancer (CAPAC) platform enables the activation of powerful cancer drugs at tumors. CAPAC utilizes a click chemistry reaction between tetrazine and trans-cyclooctene. The reaction between activator, linked to a tumor-targeting agent, and protodrug leads to the targeted activation of the drug. Here, tumor targeting is achieved by intratumoral injection of a tetrazine-modified hyaluronate (SQL70) or by infusion of a tetrazine-modified HER2-targeting antigen-binding fragment (SQT01). Monomethyl auristatin E (a cytotoxin hindered in its clinical use by severe toxicity) was modified with a trans-cyclooctene to form the protodrug SQP22, which reduced its cytotoxicity in vitro and in vivo. Treatment of SQP22 paired with SQL70 demonstrated antitumor effects in Karpas 299 and RENCA murine tumor models, establishing the requirement of click chemistry for protodrug activation. SQP22 paired with SQT01 induced antitumor effects in the HER2-positive NCI-N87 xenograft model, showing that tumor-targeted activation could be accomplished via systemic dosing. Observed toxicities were limited, with transient myelosuppression and moderate body weight loss detected. This study highlights the capabilities of the CAPAC platform by demonstrating the activity of SQP22 with two differentiated targeting approaches and underscores the power of click chemistry to precisely control the activation of drugs at tumors.

Association of OCT and OCT angiography measures with the development and worsening of diabetic retinopathy in type 2 diabetes.

OBJECTIVE: To assess if optical coherence tomography (OCT) and OCT angiography (OCTA) measures are associated with the development and worsening of diabetic retinopathy (DR) over four years. METHODS: 280 participants with type 2 diabetes underwent ultra-wide field fundus photography, OCT and OCTA. OCT-derived macular thickness measures, retinal nerve fibre layer and ganglion cell-inner plexiform layer thickness and OCTA-derived foveal avascular zone area, perimeter, circularity, vessel density (VD) and macular perfusion (MP) were examined in relation to the development and worsening of DR over four years. RESULTS: After four years, 206 eyes of 219 participants were eligible for analysis. 27 of the 161 eyes (16.7%) with no DR at baseline developed new DR, which was associated with a higher baseline HbA1c and longer diabetes duration. Of the 45 eyes with non-proliferative DR (NPDR) at baseline, 17 (37.7%) showed DR progression. Baseline VD (12.90 vs. 14.90 mm/mm2, p = 0.032) and MP (31.79% vs. 36.96%, p = 0.043) were significantly lower in progressors compared to non-progressors. Progression of DR was inversely related to VD ((hazard ratio [HR] = 0.825) and to MP (HR = 0.936). The area under the receiver operating characteristic curves for VD was AUC = 0.643, with 77.4% sensitivity and 41.8% specificity for a cut-off of 15.85 mm/mm2 and for MP it was AUC = 0.635, with 77.4% sensitivity and 25.5% specificity for a cut-off of 40.8%. CONCLUSIONS: OCTA metrics have utility in predicting progression rather than the development of DR in individuals with type 2 diabetes.

SQ3370, the first clinical click chemistry-activated cancer therapeutic, shows safety in humans and translatability across species.

Background: SQ3370 is the first demonstration of the Click Activated Protodrugs Against Cancer (CAPAC™) platform that uses click chemistry to activate drugs directly at tumor sites, maximizing therapeutic exposure. SQ3370 consists of a tumor-localizing biopolymer (SQL70) and a chemically-attenuated doxorubicin (Dox) protodrug SQP33; the protodrug is activated upon clicking with the biopolymer at tumor sites. Here, we present data from preclinical studies and a Phase 1 dose-escalation clinical trial in adult patients with advanced solid tumors ( NCT04106492 ) demonstrating SQ3370's activation at tumor sites, safety, systemic pharmacokinetics (PK), and immunological activity. Methods: Treatment cycles consisting of an intratumoral or subcutaneous injection of SQL70 biopolymer followed by 5 daily intravenous doses of SQP33 protodrug were evaluated in tumor-bearing mice, healthy dogs, and adult patients with solid tumors. Results: SQL70 effectively activated SQP33 at tumor sites, resulting in high Dox concentrations that were well tolerated and unachievable by conventional treatment. SQ3370 was safely administered at 8.9x the veterinary Dox dose in dogs and 12x the conventional Dox dose in patients, with no dose-limiting toxicity reported to date. SQ3370's safety, toxicology, and PK profiles were highly translatable across species. SQ3370 increased cytotoxic CD3 + and CD8 + T-cells in patient tumors indicating T-cell-dependent immune activation in the tumor microenvironment. Conclusions: SQ3370, the initial demonstration of click chemistry in humans, enhances the safety of Dox at unprecedented doses and has the potential to increase therapeutic index. Consistent safety, toxicology, PK, and immune activation results observed with SQ3370 across species highlight the translatability of the click chemistry approach in drug development. Trial registration: NCT04106492; 7 September 2019.

Inter-observer agreement in grading severity of diabetic retinopathy in wide-field fundus photographs.

OBJECTIVE: To examine the inter-observer agreement between two retina specialists in grading diabetic retinopathy (DR) severity in ultra-wide-field fundus photographs. METHODS: Two hundred and seventy patients with diabetes, who visited the vitreoretinal specialty at a tertiary eye care hospital, with or without DR underwent comprehensive ophthalmic examination, dilated retinal exam and Optos ultra-wide-field (UWF) retinal photography. Optos images were graded for DR severity based on the International Clinical Diabetic Retinopathy Disease Severity Scale by two retina specialists with same number of years of experience, masked to the clinical details of the participants. RESULTS: The two graders showed agreement in 229/270 images (84.8%) and disagreement in 41/270 images (15.2%). The unweighted kappa for agreement between graders was k = 0.715, SE = 0.037 and the weighted kappa was k = 0.838, SE = 0.022. No DR was identified in 170/270 (62.9%) patients, mild NPDR in 15/270 (5.6%) patients, moderate NPDR in 35/270 (12.9%) patients, severe NPDR in 4/270 (1.48%) patient and PDR in 5/270 (1.85%) patients by both graders. Disagreement was neither related to the learning curve of graders nor with the patient's age (p = 0.574), gender (p = 0.169), duration of diabetes (0.660) or the lens being phakic or pseudophakic (p = 0.171) on logistic regression. CONCLUSIONS: The impact of disagreement noted between observers in grading DR on UWF fundus photographs should be considered when utilizing UWF system in clinical studies.

Efficacy of an Automated Algorithm for Screening Diabetic Retinopathy in Gradable and Ungradable Images in Real-Time Conditions.

Background: To examine the effectiveness of a computer-assisted device (CAD) for diabetic retinopathy (DR) screening from retinal photographs at a vitreoretinal outpatient department (VR OPD), telecamps, and diabetes outpatient clinic by an ophthalmologist. In particular, the effectiveness of CAD in gradable and ungradable retinal images was examined. Methods: A total of 848 eyes of 485 patients underwent 45° retinal photographs at the VR OPD of a tertiary care hospital in southern India. A total of 939 eyes of 472 patients with diabetes were examined in the telecamps conducted in remote villages in Tamil Nadu, a state in southern India. A total of 2,526 eyes of 1,263 patients were examined in a diabetes clinic using 45° field retinal photographs. The algorithm was validated under physiological dilatation (without pharmacological dilatation) in all three arms. Results: Seventy-one percent of 848 eyes in VR OPD, 13% of 939 eyes in telecamps, and 7% of 2,526 eyes in diabetes clinic were diagnosed to have DR. The algorithm showed 78.3% sensitivity and 55.1% specificity for all images and 78.9% sensitivity and 56.8% specificity for gradable images in the VR OPD; 80.1% sensitivity and 79.2% specificity for all images and 84.8% sensitivity and 80.0% sensitivity for gradable images in telecamps; 63.0% sensitivity and 79.6% specificity for all images and 63.2% sensitivity and 78.1% specificity for gradable images in the diabetes clinic. The algorithm had an overall accuracy of 76.4%. The ungradable rate was variable. Conclusion: The algorithm performs equally well in identifying DR from gradable and ungradable photographs and may be used for DR screening in a rural setting with limited or no access to eye care.

Early retinal functional alteration in relation to diabetes duration in patients with type 2 diabetes without diabetic retinopathy.

To examine the retinal structure and function in relation to diabetes duration and glycemia in patients without diabetic retinopathy (DR). 85 adults with type 2 diabetes without DR or macular edema underwent dilated indirect ophthalmoscopy, optical coherence tomography (OCT), ultra-wide field fundus photography, multifocal electroretinography (mfERG) and HbA1C assessment. Patients were stratified as those with diabetes duration < 10 years and ≥ 10 years. Right eyes of all participants were analyzed. mfERG was analysed as ring 12, 34, 56. No significant differences were noted in OCT-derived retinal thickness measures between groups. mfERG P1 latencies were delayed, and amplitudes (nV/deg2) were reduced in all three rings in those with diabetes duration ≥ 10 years vs. < 10 years, with significant correlations to diabetes duration in all rings. Logistic regression showed that duration of diabetes ≥ 10 years was associated with greater age (odds ratio (OR) 1.081, 95% CI 1.022, 1.143) and lower P1 amplitudes in the middle ring (OR 0.924, 95% CI 0.854, 0.999). No significant correlations were observed between HbA1c and retinal measures. In the absence of DR, early retinal functional alterations are detectable on mfERG in patients with longer diabetes duration, but with no difference in OCT-derived retinal thickness.

Sacral osteomyelitis as a rare cause of anorectal pain several years following treatment for rectal carcinoma.

A 66-year-old man was treated for a moderately differentiated T3 N1 M0 adenocarcinoma of the rectum in 2015 with preoperative short course radiotherapy, anterior resection and then adjuvant chemotherapy with oxaliplatin and capecitabine. Following ileostomy reversal, he complained of intense, unremitting anorectal pain. After repeated scans, computed tomography (CT) showed findings suggestive of a longstanding anastomotic leak. Subsequent, magnetic resonance imaging (MRI) revealed osteomyelitis of the sacrum, with the development of sacral osteomyelitis in this context unusual. Our case highlights the importance of appropriate radiological imaging and that clinicians should consider osteomyelitis as a differential diagnosis in patients presenting with severe anorectal pain after treatment for rectal cancer.

Online Isha Upa Yoga for student mental health and well-being during COVID-19: A randomized control trial.

College students experienced increased stress and anxiety during the COVID-19 pandemic. This study evaluated the effect of brief online Isha Upa Yoga modules on undergraduates' mental health and well-being. Randomized control trial (RCT) with waitlist control crossover (N = 679). The intervention group was instructed to learn and practice the modules daily for 12 weeks. At the end of the 4-week RCT, the control group was instructed to learn and practice the modules for the remaining 8 weeks. Primary outcomes included stress and well-being. Secondary outcomes included anxiety, depression, resilience, positive affect and negative affect. Linear mixed-effects models were used for analyses. Isha Upa Yoga significantly reduced stress (Group [intervention, control] × Time [baseline, Week 4] interaction, p = .009, d = .27) and increased well-being (Group × Time interaction p = .002, d = .32). By the study's end, the intervention and control groups experienced significant improvements in well-being (p < .001, p < .001), stress (p < .001, p < .001), anxiety (p < .001, p < .001), depression (p < .001, p = .004), positive affect (p = .04, p < .001), and negative affect (p < .001, p < .001). Online Isha Upa Yoga shows promise for mitigating the pandemic's negative impact on undergraduates' mental health and improving their well-being.

Zone-wise examination of optical coherence tomography features and their correspondence to multifocal electroretinography in eyes with nonproliferative diabetic retinopathy.

PURPOSE: To examine (1) the retinal structure by optical coherence tomography (OCT) and function by means of multifocal electroretinography (mfERG) in eyes with and without nonproliferative diabetic retinopathy (NPDR) (2) for correspondence between local retinal function and OCT zones with retinal lesions. METHODS: One hundred and thirty-two eligible participants (30 with nonproliferative DR (NPDR) and 102 with diabetes with no DR) underwent comprehensive ophthalmic examination, optical coherence tomography for retinal thickness measures, mfERG, and ultra-wide field fundus photography. OCT Early Treatment Diabetic Retinopathy Study (ETDRS) grid was overlaid on to mfERG plots. RESULTS: Those with NPDR had significantly thicker full retinal measures in the nine (ETDRS) zones compared to no DR. mfERG P1 latencies in rings 1-6 were significantly delayed, while the response densities in rings 4-6 were lower in the NPDR group. Significant negative correlation was noted between OCT thickness and mfERG P1 response densities in many ETDRS zones. Significant positive correlation was noted between P1 latencies and OCT thickness in a few zones. The combination of cystic spaces, microaneurysms, and hard exudates were present in all zones and were associated with a decrease in P1 response densities compared to no lesions. Reduced P1 response densities were associated with a sporadic delay in the mfERG latencies and vice versa. The number of lesions did not show correspondence to the mfERG measures. CONCLUSIONS: In eyes with NPDR, retinal function is differentially correlated with the DR lesions on OCT and can be assessed using multimodal imaging modalities.

Retinal structure-function correlation in type 2 diabetes.

OBJECTIVE: To examine the relationship of visual function as assessed by visual acuity, contrast sensitivity, and multifocal electroretinography (mfERG) to macular structural and microvascular measures on optical coherence tomography (OCT) and angiography (OCTA) in individuals with diabetes. METHODS: This is a prospective observational study conducted at a tertiary eye care centre in India. Right eyes of 121 adults with type 2 diabetes with no diabetic retinopathy (DR), mild or moderate nonproliferative DR (NPDR) were examined. Severe NPDR, proliferative DR and diabetic macular oedema were excluded. Participants underwent assessment of glycated haemoglobin (HbA1C), blood pressure, best corrected visual acuity (LogMAR), contrast sensitivity (CS), mfERG, ultrawide field fundus photography, OCT and OCTA. Correlations were assessed by Spearman's rank correlation (rho). RESULTS: Of the total of 121 eyes, 89 had No DR, 32 had mild to moderate NPDR. In the No DR group, the LogMAR acuity was significantly and negatively correlated to central subfoveal thickness (CST) (rho = -0.420), macular vessel density (rho = -0.270) and perfusion (rho = -0.270). (ii) Contrast sensitivity correlated to foveal avascular zone circularity (rho = 0.297); (iii) mfERG P1 response densities were better with higher macular perfusion index (rho = 0.240). In the NPDR group, the LogMAR acuity also showed a significant negative correlation to CST (rho = -0.379). Other correlations were not significant. CONCLUSION: Retinal and visual functional changes are evident in diabetic patients with No DR and are correlated to subclinical retinal structural changes detectable using multimodal imaging.

Assessment of optical coherence tomography angiography and multifocal electroretinography in eyes with and without nonproliferative diabetic retinopathy.

PURPOSE: To examine (i) the retinal structure and function using optical coherence tomography angiography (OCTA) and multifocal electroretinography (mfERG), respectively, in eyes with and without nonproliferative diabetic retinopathy (NPDR), (ii) and their interrelationship between retinal structure (OCTA) and function (mfERG) in the two groups independently. METHODS: This was a prospective observational study. One hundred twenty-one eligible participants with type 2 diabetes with No DR (n = 89), or with mild or moderate NPDR (n = 32) underwent ophthalmic examination, ultrawide field-view fundus photography, OCTA, and mfERG. Group differences were assessed using a Mann-Whitney U test. Correlations were assessed using Spearman's rho. RESULTS: There were no significant differences in OCTA measures between the two groups. The mfERG P1 implicit times (rings 1-6) were significantly delayed and P1 response densities in rings 5 and 6 were significantly lower in participants with NPDR compared to those with No DR. In those with No DR, P1 implicit times in almost all rings were delayed in relation to lower vessel density and perfusion (maximum variance noted was 13%). In individuals with NPDR, the P1 response density in rings 2 and 3 showed a positive nonsignificant correlation with macular perfusion. CONCLUSION: In those with diabetes with No DR, retinal neuronal function is influenced by lower macular vessel density and perfusion. The retinal neuronal function is abnormal in individuals with NPDR compared to those with No DR and is not correlated with OCT angiometric measures, suggesting the likelihood of a different retinal structural correlate.

Distribution and risk factors of postoperative endophthalmitis in people with diabetes.

PURPOSE: To evaluate (i) the distribution of postoperative endophthalmitis (POE) in patients who underwent cataract surgery, (ii) risk factors in diabetic versus nondiabetic patients, and (iii) distribution of POE in those who had undergone rapid reduction of preoperative blood sugar levels versus those with normal blood sugar levels. METHODS: Medical records were reviewed from January 1995 to July 2021. In total, 391 eyes of 391 patients who developed POE after cataract surgery were studied. Patients with POE were divided into Group A, patients with diabetes (n = 128), and Group B, patients without diabetes (n = 263), and the associations of various clinical factors in the two groups were studied. Patients with diabetes with raised random blood sugars (RBS) preoperatively were subjected to a rapid reduction of blood sugar (RBS <200 mg%) to be considered eligible for surgery. Microbiological profile of patients was examined. RESULTS: The cumulative incidence of POE over 26 years was 0.09%. Those who underwent a rapid reduction in preoperative blood sugar levels had higher rates of POE (53.1%) compared with (46.9%) those with blood sugar levels under control (P = 0.486). Men with diabetes had 1.634 times higher odds of POE (P = 0.048), and those with diabetes and hypertension had 3.961 times greater odds of having POE (P < 0.001) when adjusted for age, alcohol, smoking, and socioeconomic strata and presence of posterior capsule rupture. Positive culture results were observed in 45/128 (35%) patients with diabetes and 71/263 (27%) patients without diabetes. Staphylococcus epidermidis was the most commonly identified organism and was detected in 10/45 (22%) in those with diabetes and 21/71 (29%) in those without diabetes of all the culture-positive cases. CONCLUSION: In patients with POE, the odds are greater for men with diabetes, those with a history of hypertension, as well as those who undergo a rapid reduction of preoperative blood sugar.

Comparison of Two Ultra-Widefield Cameras With High Image Resolution and Wider View for Identifying Diabetic Retinopathy Lesions.

Purpose: To compare the effectiveness of the Optos P200dTx and Zeiss Clarus 500 fundus cameras in detecting diabetic retinopathy (DR) lesions. Methods: A cross-sectional study was conducted among 243 patients with clinically diagnosed diabetes mellitus who were referred for an eye examination from two tertiary eye care centers in Chennai, India. Patients underwent DR screening based on mydriatic fundal images acquired by both fundal cameras. Fundal images from the two separate devices for each eye were compared based on accurately identified pathological retinal lesions with respect to type and location. Results: When studying lesions of the central retina, they were better identified by the Zeiss Clarus compared with the Optos P200dTx, with six out of eight being statistically significant (P < 0.05). However, lesions of the mid-peripheral retina and peripheral retina were better identified by the Optos P200dTx than the Zeiss Clarus, with three out of eight lesions and five out of eight lesions being statistically significant (P < 0.05), respectively. Based on the color and size of lesions, the Optos P200dTx had a higher chance (59.6%) of missing white lesions than did the Zeiss Clarus (17%) (P < 0.0001). Consequently, small- and medium-sized lesions were missed more by the Optos P200dTx (30.72% and 32.63%, respectively) than the Zeiss Clarus (22.3% and 19.30%, respectively). Conclusions: The capability of detecting or missing a particular DR lesion among diabetics differed between the two cameras based on effective field of view, resolution, and the retinal zone being imaged. Translational Relevance: The choice of which ultra-widefield camera to be used for screening DR can be based on the greater prevalence of central versus peripheral retinal lesions noted in the patient population seen in a clinical practice.

Correction: Click activated protodrugs against cancer increase the therapeutic potential of chemotherapy through local capture and activation.

[This corrects the article DOI: 10.1039/D0SC06099B.].

Click activated protodrugs against cancer increase the therapeutic potential of chemotherapy through local capture and activation.

A desired goal of targeted cancer treatments is to achieve high tumor specificity with minimal side effects. Despite recent advances, this remains difficult to achieve in practice as most approaches rely on biomarkers or physiological differences between malignant and healthy tissue, and thus benefit only a subset of patients in need of treatment. To address this unmet need, we introduced a Click Activated Protodrugs Against Cancer (CAPAC) platform that enables targeted activation of drugs at a specific site in the body, i.e., a tumor. In contrast to antibodies (mAbs, ADCs) and other targeted approaches, the mechanism of action is based on in vivo click chemistry, and is thus independent of tumor biomarker expression or factors such as enzymatic activity, pH, or oxygen levels. The CAPAC platform consists of a tetrazine-modified sodium hyaluronate-based biopolymer injected at a tumor site, followed by one or more doses of a trans-cyclooctene (TCO)-modified cytotoxic protodrug with attenuated activity administered systemically. The protodrug is captured locally by the biopolymer through an inverse electron-demand Diels-Alder reaction between tetrazine and TCO, followed by conversion to the active drug directly at the tumor site, thereby overcoming the systemic limitations of conventional chemotherapy or the need for specific biomarkers of traditional targeted therapies. Here, TCO-modified protodrugs of four prominent cytotoxics (doxorubicin, paclitaxel, etoposide and gemcitabine) are used, highlighting the modularity of the CAPAC platform. In vitro evaluation of cytotoxicity, solubility, stability and activation rendered the protodrug of doxorubicin, SQP33, as the most promising candidate for in vivo studies. In mice, the maximum tolerated dose (MTD) of SQP33 in combination with locally injected tetrazine-modified biopolymer (SQL70) was determined to be 19.1-times the MTD of conventional doxorubicin. Pharmacokinetics studies in rats show that a single injection of SQL70 efficiently captures multiple SQP33 protodrug doses given cumulatively at 10.8-times the MTD of conventional doxorubicin with greatly reduced systemic toxicity. Finally, combined treatment with SQL70 and SQP33 (together called SQ3370) showed antitumor activity in a syngeneic tumor model in mice.

Dendritic cells support a proliferative antigen-specific T-cell response in the presence of poly(lactic-co-glycolic acid).

Biomaterials are known to modulate immune cell functions, which subsequently determine the host inflammatory and immune responses. Poly(lactic-co-glycolic acid) or PLGA, a biodegradable and biocompatible biomaterial, induces a pro-inflammatory, mature phenotype in antigen presentation cells, namely dendritic cells (DCs) in vitro. In vivo, PLGA can boost the humoral immune response to a co-delivered model antigen, a phenomenon known as the PLGA-adjuvant effect. This study elucidates the link between PLGA's effect on the DC phenotype in vitro and its adjuvant effect in vivo using the CD11c-DTR mouse model. These mice undergo conditional ablation of DCs upon treatment with diphtheria toxin. To measure immune activation, the mice were first given ovalbumin (OVA)-reactive T cells from OT-II/OT-I mice. Later, the same mice received subcutaneous OVA-loaded PLGA scaffold implants. In response to the scaffold implants, OVA-reactive OT-II CD4+ T cells showed decreased proliferation in the absence of CD11c+ DCs, indicating an attenuation of the PLGA-adjuvant effect. Furthermore, PLGA may also influence the antigen cross-presentation function of DCs, as evident with the lowered OVA-reactive OT-I CD8+ T-cell response. Understanding the immunomodulatory ability of biomaterials in the context of DCs will aid in designing improved DC-based immunotherapies against infectious diseases and cancer.

Relationship between triglyceride glucose index, retinopathy and nephropathy in Type 2 diabetes.

Aims: To explore the relationship between TyG index, diabetic retinopathy (DR) and nephropathy. Methods: This was a cross-sectional observational study that examined 1413 subjects with type 2 diabetes (both known and newly diagnosed). Subjects underwent a detailed standard evaluation to detect diabetic retinopathy (fundus photography) and nephropathy (defined as urinary albumin excretion ≥ 30 mg/24 h). The TyG index was calculated as ln (fasting triglycerides (mg/dL) × fasting glucose (mg/dL)/2) and stratified into 4 quartiles (TyG-Q). The baseline characteristics of the study population in the four TyG-Q (Q1 (≤7.3) n = 349, Q2 (>7.3 to ≤ 7.5) n = 358, Q3 (>7.5 to ≤ 8.0) n = 354, and Q4 (>8.0) n = 352) were analysed. Variables associated with the presence of DR and nephropathy were assessed using a stepwise binary logistic regression analysis. Results: The presence of DR was associated with higher TyG index (OR = 1.453, P =.001) and longer duration of diabetes (OR = 1.085, P < .001). The presence of nephropathy was associated with a higher TyG index (OR = 1.703, P < .001), greater age (OR = 1.031, P < .001), use of insulin (OR = 1.842, P = .033), higher systolic BP (OR = 1.015, P < .001), and the presence of DR (OR = 3.052, P < .001). Higher TyG-Q correlated with the severity of DR (P = .024), presence of nephropathy (P = .001), age (P < .001) and diastolic blood pressure (P = .006). Conclusions: A higher TyG index is associated with the presence of retinopathy and nephropathy in individuals with diabetes and could be used for monitoring metabolic status in clinical settings.

Contrast-Sensitivity Function and Photo Stress-Recovery Time in Prediabetes.

PURPOSE: The purpose of this study was to assess contrast sensitivity and macular function test in prediabetes. METHODS: Participants aged 25-45 years with or without diabetes were enrolled and classified as normal, prediabetic, and diabetic based on their HbA1C values. They underwent a comprehensive eye examination, and those with diabetic retinopathy, cataract, glaucoma, and high myopia were excluded. Participants with best-corrected visual acuity of 0 logMAR were included. Contrast-sensitivity function (CSF) was measured using a Pelli-Robson chart, and photo stress-recovery time (PSRT) assessed using direct ophthalmoscopy for the 70 eligible participants. Mean values were compared among the three groups. DESIGN: This was a cross-sectional observational study. RESULTS: In the 70 participants, mean CSF was 1.71±0.10, 1.64±0.11, and 1.61±0.08 log units in the normal, prediabetic, and diabetic groups, respectively (p<0.001). Similarly, PSRT was found to be 35.80 seconds, 41.63 seconds, and 47.77 seconds in the normal, prediabetic, and diabetic groups, respectively (p<0.001). CONCLUSION: The data suggested that reduced CSF and delayed PSRT seen in subjects with prediabetes could give valuable clinical insight into early changes before diabetes and microvascular damage is incurred. A future study with a larger sample could help substantiate the results.

Rapid Corneal Nerve Fiber Loss: A Marker of Diabetic Neuropathy Onset and Progression.

OBJECTIVE: Corneal nerve fiber length (CNFL) represents a biomarker for diabetic distal symmetric polyneuropathy (DSP). We aimed to determine the reference distribution of annual CNFL change, the prevalence of abnormal change in diabetes, and its associated clinical variables. RESEARCH DESIGN AND METHODS: We examined 590 participants with diabetes (399 with type 1 diabetes [T1D] and 191 with type 2 diabetes [T2D]) and 204 control patients without diabetes with at least 1 year of follow-up and classified them according to rapid corneal nerve fiber loss (RCNFL) if CNFL change was below the 5th percentile of the control patients without diabetes. RESULTS: Control patients without diabetes were 37.9 ± 19.8 years old, had median follow-up of three visits over 3.0 years, and mean annual change in CNFL was -0.1% (90% CI -5.9% to 5.0%). RCNFL was defined by values exceeding the 5th percentile of 6% loss. Participants with T1D were 39.9 ± 18.7 years old, had median follow-up of three visits over 4.4 years, and mean annual change in CNFL was -0.8% (90% CI -14.0% to 9.9%). Participants with T2D were 60.4 ± 8.2 years old, had median follow-up of three visits over 5.3 years, and mean annual change in CNFL was -0.2% (90% CI -14.1% to 14.3%). RCNFL prevalence was 17% overall and was similar by diabetes type (64 T1D [16.0%], 37 T2D [19.4%], P = 0.31). RNCFL was more common in those with baseline DSP (47% vs. 30% in those without baseline DSP, P = 0.001), which was associated with lower peroneal conduction velocity but not with baseline HbA1c or its change over follow-up. CONCLUSIONS: An abnormally rapid loss of CNFL of 6% per year or more occurs in 17% of diabetes patients. RCNFL may identify patients at highest risk for the development and progression of DSP.

Controlled Delivery of Immunomodulators from a Biomaterial Scaffold Niche to Induce a Tolerogenic Phenotype in Human Dendritic Cells.

Engineering a regulatory phenotype in dendritic cells (DCs) is a potential approach to circumvent an immune response against self-antigens in autoimmunity or alloantigens in allograft rejection. Cell microenvironments influence the differentiation of DC precursors into either proinflammatory/immunostimulatory or tolerogenic/regulatory DCs. Biomaterial-based vehicles can be used to re-engineer cell microenvironments and re-educate the DC phenotype. This study presents the development and validation of a biomaterial-based multicomponent immunomodulatory (MI) scaffold for the purpose of promoting a tolerogenic/regulatory DC phenotype. Glutaraldehyde-crosslinked gelatin microparticles, loaded with specific immunomodulators, were embedded into a porous agarose scaffold. Using the Weibull equation and the Bayesian approach, an empirical mathematical model was derived from the release profile data of "model" molecules. The scaffold design was generated from the model to achieve distinct temporal release profiles of the loaded immunomodulator(s): granulocyte monocyte colony-stimulating factor (GM-CSF), dexamethasone (DEX), and/or peptidoglycan (PGN). The MI scaffold-treated DCs (MI DCs) showed an increase in the expression of tolerogenic markers such as surface immunoglobulin-like transcript 3 (ILT-3) and secreted interleukin-10 (IL-10), with a simultaneous decrease in maturation markers such as CD86 and secreted interferon-γ (IFN-γ). In cell culture studies, these MI DCs were able to suppress T-cell proliferation. This approach is expected to enhance the generation of endogenous regulatory DCs when applied in vivo. This technology serves as a basis for future immunotherapeutic applications in the autoimmunity and allogeneic therapies. It also shows that empirical mathematical modeling can be used to engineer scaffold designs for distinct temporal release of one or more immunomodulators.