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.

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.

Four-year Incident Neuropathy and its Risk Factors in Subjects with Type 2 Diabetes.

OBJECTIVE: The study assessed the four-year incidence of diabetic peripheral neuropathy (DPN) and the risk factors that can predict incident neuropathy in a south Indian population with type 2 diabetes. RESEARCH DESIGN AND METHODS: 1175 diabetic individuals were identified with known diabetes at baseline. At baseline, individuals underwent assessment of fasting plasma glucose and HbA1c levels, body mass index, waist-hip ratio, blood pressure, blood cholesterol and lipid levels, and ophthalmic evaluation including visual acuity, specular microscopy of the corneal endothelium, cataract grading and diabetic retinopathy assessment. Subjects were re-examined after four years for the assessment of incident neuropathy; 713 individuals were found eligible at follow-up. The presence of neuropathy was assessed at baseline and at follow-up and was defined as a Vibration Perception Threshold of ≥ 20 Volts. RESULTS: : The four-year incidence of any neuropathy was 28.4%. Factors predictive of incident diabetic neuropathy were greater age at baseline (OR =1.068), higher body mass index (OR =1.034), presence of diabetic retinopathy (OR =4.879) and lower socioeconomic status (OR =4.841), when adjusted for several potential confounding factors. CONCLUSION: The four-year incidence of diabetic neuropathy in a south Indian population with type 2 diabetes is 28% and can be predicted by ophthalmic and clinical variables. These factors may be utilized in the assessment, monitoring and intervention in individuals with diabetes in an effort to prevent or delay the development of diabetic peripheral neuropathy.

Optical coherence tomography predicts 4-year incident diabetic neuropathy.

PURPOSE: To examine the capability of optical coherence tomography-derived retinal thickness measures in detecting 4-year incident diabetic peripheral neuropathy (DPN). METHODS: 145 eyes of 145 participants with diabetes but no DPN at baseline were examined for incident DPN. HbA1c levels, nephropathy, neuropathy (DPN), cardiovascular measures, and various retinal thickness measures were examined at baseline and after 4 years. Incidence of DPN was defined as newly developed DPN at follow-up. Baseline factors were assessed by univariate and a step-wise multiple logistic regression, and the predictors were examined for diagnostic capabilities. RESULTS: Of the 145 participants without DPN at baseline, 51 had developed DPN when examined after 4 years (35% incidence). Of the ophthalmic variables, the mean (S.D.) of the overall thickness in the parafovea at baseline was 315 (18) µm in the no DPN group and 306 (18) µm in the 'incidence' group, and the differences were significant, p = 0.005. The superior hemisphere parafovea (mean (S.D.): 318 (17) µm vs 310 (20) µm, p = 0.02) and inferior hemisphere parafovea (313 (19) µm vs 302 (18) µm, p = 0.002) were different in the incident DPN group compared with the no DPN group. When adjusted for age, retinal thickness in the parafovea (AUC = 0.65, p = 0.003, 86% sensitivity and 44% specificity at 321 µm criterion), and body mass index or BMI (AUC = 0.65, p = 0.003, 49% sensitivity and 83% specificity at 29.3 kg m-2 criterion) at baseline were significant predictors for 4-year incident DPN. CONCLUSIONS: A lower retinal thickness at the parafovea and a higher BMI can predict 4-year incident neuropathy in patients with diabetes, with acceptable diagnostic accuracies. This OCT-derived measure may serve as a potential ophthalmic marker in the screening of patients at risk of developing DPN.

Influence of serum lipids on the incidence and progression of diabetic retinopathy and macular oedema: Sankara Nethralaya Diabetic Retinopathy Epidemiology And Molecular genetics Study-II.

IMPORTANCE: The importance of lipids on incidence and progression of diabetic retinopathy has not been studied in the Indian population. BACKGROUND: To elucidate the influence of serum lipid control on the incidence and progression of diabetic retinopathy and diabetic macular oedema in subjects with type 2 diabetes. DESIGN: Population-based longitudinal observational study in a hospital setting. PARTICIPANTS: Eight hundred ninety subjects were examined at baseline and follow-up. METHODS: Diabetic retinopathy was graded per Modified Early Treatment Diabetic Retinopathy Study scales; 45°, 4-field dilated stereoscopic digital photography was performed with an additional 30°, 7-field for those who had retinopathy. Macular oedema was evaluated per Proposed International Clinical Diabetic Retinopathy and Diabetic Macular Oedema Disease Severity Scales. MAIN OUTCOME MEASURES: Association of serum lipids and incidence and progression of diabetic retinopathy. RESULTS: Poor control of total cholesterol was associated with the incidence of sight-threatening retinopathy (odds ratio = 7.2 [95% confidence interval: 1.5-34.3], P = 0.012) and macular oedema (odds ratio = 5.5 [95% confidence interval: 1.4-27.4], P = 0.037) after adjusting for potential confounders. Poor control of triglycerides was associated with progression to proliferative diabetic retinopathy (odds ratio = 3.2 [95% confidence interval: 1.1-10.5], P = 0.048). Risk for incident macular oedema (P = 0.041) and progression to proliferative diabetic retinopathy (P = 0.028) was greater when all lipid types were abnormal. CONCLUSIONS AND RELEVANCE: Poor control of lipids is a risk factor for incidence of and progression to late stages of retinopathy. Abnormal levels of all lipid types are associated with risk of incident macular oedema and progression to proliferative diabetic retinopathy.

The association of smokeless tobacco use and pack-years of smokeless tobacco with age-related macular degeneration in Indian population.

AIM: To explore the association of use versus no use and the influence of pack-year use of smokeless tobacco with that of early and late age-related macular degeneration (AMD) in rural and urban south Indian population. We hypothesized that the use and pack-years of use would be significantly associated with both early and late AMD. We therefore sought to examine subjects who gave a history of using smokeless tobacco and we quantified the usage as pack-years, to examine the association with that of early and late AMD. MATERIALS AND METHODS: This was part of Sankara Nethralaya: Rural-Urban Age-related Macular degeneration study (SN-RAM study), which was conducted between 2007 and 2010. Subjects aged 60 years or older or those turning 60 in the present calendar year, with a history of using smokeless tobacco were noted along with duration and number of packs used per day. Smokeless tobacco was defined as chewed-tobacco (loose leaves) and/or snuff (finely chopped tobacco). Subjects underwent detailed ophthalmic evaluation including cataract grading using the Lens Opacities Classification System (LOCS III), 45° 4-field stereoscopic fundus photography and AMD evaluation. Pack-years of smokeless tobacco use was stratified as <15, 15-34 and ≥35 years; the association of tobacco use and pack-years of use with that of early and late AMD was examined. A p value of < 0.05 was considered statistically significant. RESULTS: The number of smokeless tobacco users was significantly higher in rural (n = 767) than in urban groups (n = 281), p < 0.001. Of the 1048 users, 238 subjects (23%) provided details regarding quantification of use. There were no significant differences in the pack-years between rural and urban areas, p = 0.756 or that between AMD and no AMD, p = 0.562. Use of smokeless tobacco compared with no use was significantly associated with late AMD, OR= 3.178, 95%CI: 1.095, 9.227, p = 0.033, when adjusted for age, gender, rural-urban differences, presence of diabetes, socioeconomic status, systolic and diastolic blood pressure, total cholesterol, low-density and high-density lipoprotein levels. The association was not significant for early AMD, p = 0.582. The pack-years of use did not show a statistically significant association with early or late AMD. Furthermore, out of the 1048 subjects, 547 reported as using areca nut. Of which, 415 (75.8%) subjects had no AMD, 119 (21.7%) showed evidence of early AMD and 13 (2.4%) had late AMD. There was no significant association between the use of areca nut and early AMD, (X2 (1, N = 930) = 2.345, p = 0.126) or with that of late AMD (X2 (1, N = 761) = 0.075, p = 0.785). CONCLUSIONS: Smokeless tobacco use compared with no use, is associated with late AMD, regardless of the pack-years of use. Tobacco use is a modifiable risk factor. Efforts to reduce or stop the use of smokeless tobacco is indicated in an effort to prevent vision loss with respect to late AMD.

Retinal thickness profile of individuals with diabetes.

PURPOSE: To examine the retinal thickness profiles of individuals with and without diabetic retinopathy (DR). METHODS: Full retinal thickness in the central zone, overall and hemisphere thicknesses of the parafovea and perifovea, ganglion cell complex (GCC) thickness and retinal nerve fibre layer (RNFL) thickness were assessed in 185 individuals using spectral domain optical coherence tomography (88 individuals with diabetes but no DR, 55 with DR, and 42 non-diabetic controls). The DR group comprised of 60% of participants with very mild non-proliferative diabetic retinopathy (NPDR) (representing microaneurysms only) and 40% with mild NPDR (hard exudates, cotton-wool spots, and/or mild retinal haemorrhages). Regression analysis was performed to determine the factors associated with retinal tissue thickness, taking into account, age, sex, presence of DR, duration of diabetes, HbA1c levels and type of diabetes. RESULTS: The mean (S.D.) of the overall parafoveal thickness was 306 (16) in the DR group and 314 (14) in the control group (p = 0.02). The mean (S.D.) of the superior hemisphere parafoveal thickness was 309 (16) in the DR group and 318 (14) in the control group (p = 0.02). The mean (S.D.) of the inferior hemisphere parafoveal thickness was 303 (17) in the DR group and 311 (15) in the control group (p = 0.02). There were no significant differences in retinal thickness between groups in the central zone (p = 0.27) or perifovea (p > 0.41). Neither the overall nor the hemisphere RNFL (p > 0.75) and GCC thickness (p > 0.37) were significantly different between the groups. Regression analysis revealed that parafoveal thickness in diabetic individuals was reduced in association with presence of DR (B = -5.9 µm, p = 0.02) and with advancing age (B = -4.5 µm, p = 0.004, for every 10 year increase in age) when adjusted for sex, duration of diabetes, HbA1c levels and type of diabetes. CONCLUSION: The inner macula is thinner in the presence of clinical signs of diabetic retinopathy and is compounded by advancing age. The influence of any macular oedema or that by cotton-wool spots could not be ruled out and may still confound these results.

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.

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.

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.

Antifungal activity of phenyl derivative of pyranocoumarin from Psoralea corylifolia L. seeds by inhibition of acetylation activity of trichothecene 3-o-acetyltransferase (Tri101).

Antifungal activity of petroleum ether extract of Psoralea corylifolia L. seed, tested against Fusarium sp. namely, Fusarium oxysporum, Fusarium moniliforme, and Fusarium graminearum, was evaluated by agar well diffusion assay. The chromatographic fractionation of the extract yielded a new phenyl derivative of pyranocoumarin (PDP). The structure of the PDP was confirmed using spectroscopic characterization (GC-MS, IR, and NMR), and a molecular mass of m/z 414 [M-2H](+) with molecular formula C(27)H(28)O(4) was obtained. The PDP had a potent antifungal activity with a minimum inhibitory concentration of 1 mg/mL against Fusarium sp. Molecular docking using Grid-Based Ligand Docking with Energetics (GLIDE, Schrodinger) was carried out with the Tri101, trichothecene 3-O-acetyltransferase, as target protein to propose a mechanism for the antifungal activity. The ligand PDP showed bifurcated hydrogen bond interaction with active site residues at TYR 413 and a single hydrogen bond interaction at ARG 402 with a docking score -7.19 and glide energy of -45.78 kcal/mol. This indicated a strong binding of the ligand with the trichothecene 3-O-acetyltransferase, preventing as a result the acetylation of the trichothecene mycotoxin and destruction of the "self-defense mechanism" of the Fusarium sp.

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.

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.

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.

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.

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.

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.