Comparison between opposite clear corneal incision versus toric intraocular lens in correcting astigmatism.

PURPOSE: To compare the visual outcomes and efficacy of opposite clear corneal incision (OCCI) and toric intraocular lens (IOL) implantation in correcting preexisting astigmatism (PEA) in patients undergoing phacoemulsification. METHODS: This prospective interventional comparative study was conducted between June 2022 and January 2023 in patients having cataract with PEA undergoing phacoemulsification. Patients were divided into two groups - group A underwent phacoemulsification with OCCI and group B underwent phacoemulsification with toric IOL implantation. Uncorrected distance visual acuity (UDVA), manifest refractive cylinder, and corneal astigmatism using corneal tomography were measured preoperatively and at 6 weeks postoperatively. The eyes were categorized into three groups with PEA ranging from 1 to 1.5 D, 1.6 to 2 D, and 2.1 to 3 D. Depending upon the white-to-white corneal diameter, the eyes were also categorized into four groups with corneal diameter ranging from 10.5 to 10.9 mm, 11 to 11.4 mm, 11.5 to 11.9 mm, and 12 to 12.4 mm. RESULTS: Sixty eyes of 60 patients were studied. At postoperative 6 weeks, 83.3% (25 eyes) in the OCCI group and 96.7% (29 eyes) in the toric IOL group achieved UDVA of 6/9 or better. No statistically significant difference was noted between the groups (P = 0.37). The reduction in mean corneal astigmatism was 0.63 ± 0.37 D in the OCCI group and 0.15 ± 0.12 D in the toric IOL group (P < 0.001). The residual mean refractive cylinder was 0.60 ± 0.38 D in the OCCI group and 0.05 ± 0.15 D in the toric IOL group at 6 weeks (P = 0.007). CONCLUSION: Both OCCI and toric IOL are effective in correcting PEA. However, in a resource-limited setting, OCCI is a better alternative surgical option for correcting astigmatism of 1-1.5 D during phacoemulsification without requiring additional skills or instruments.

Unravelling the molecular mechanistic pathway underlying the anticancer effects of kaempferol in colorectal cancer: a reverse pharmacology network approach.

Colorectal cancer (CRC) is the third most diagnosed and highly fatal malignancy, presenting serious health concerns worldwide. The search for an effective cure for CRC is challenging and poses a serious concern. Kaempferol is a potent anti-cancerous bioactive compound often suggested for treating various cancers, including CRC. However, its underlying molecular mechanism against CRC remains unclear. The present study delves into kaempferol's molecular pathways and underlying molecular mechanisms against CRC targets. The target protein-coding genes for kaempferol were retrieved, and the CRC-associated genes were curated. Twelve common targets with a disease specificity index of > 0.6 were validated for their protein expression at different stages of CRC. Over-expressed USP1, SETD7, POLH, TDP1 and RACGAP1 were selected for further studies. The binding affinities of kaempferol to the corresponding proteins were evaluated using molecular docking and Molecular Dynamics (MD) simulations. SETD7 exhibited the highest binding affinity with the lowest binding energy (- 8.06 kcal/mol). Additionally, the MD simulation, and MM-PBSA conferred SETD7-kaempferol complex had the least root-mean-square deviation with lower interaction energy and higher conformational stability. The protein-protein interaction of SETD7 constructed revealed direct interactors, namely, DNMT1, FOXO1, FOXO3, FOXO4, H3-3B, H3-4, H3C12, H3C13, SETD7, SIRT1 and TP53, have a potential role in cancer progression through FOXO signalling. In summary, our study revealed kaempferol's multi-target and synergistic effect on multiple CRC targets and its underlying mechanisms. Finally, the study recommends in-vitro and in-vivo trials for validation of anti-cancerous drugs for CRC.

Renal Functional Reserve in Acute Kidney Injury Patients Requiring Dialysis.

The incidence of acute kidney injury (AKI) has increased in the recent past. Patients with AKI have an increased risk of mortality. They are also at increased risk of developing chronic kidney disease (CKD). AKI can lead to irreversible loss of renal function despite complete clinical recovery. Currently, no tools are available to diagnose this subclinical loss of renal function. Renal functional reserve (RFR) can serve as an essential tool for analyzing this subclinical loss of renal function, and patients with loss of RFR post-AKI may be closely followed for the development of CKD. This prospective observational study, conducted at the Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), aimed to investigate RFR in 223 patients with AKI requiring dialysis. The study excluded patients with CKD and obstructive uropathy. Methods included RFR assessment three months post-AKI recovery, utilizing technetium-99m (Tc-99m) diethylenetriaminepentaacetic acid (DTPA) plasma clearance during amino acid infusion. Statistical analyses and logistic regression were applied, receiving ethical approval. Results revealed a high in-hospital mortality rate of 78.02%, associated with elevated Sequential Organ Failure Assessment (SOFA) scores. Among 24 patients with complete AKI recovery, the RFR at three months was 10.06% (interquartile range (IQR) 5.60-20.15), with the measured GFR significantly lower than the estimated glomerular filtration rate (GFR). The study concludes that AKI requiring dialysis is linked to high mortality and emphasizes the predictive value of SOFA scores. Additionally, RFR testing at three months post-recovery provides insights into potential long-term impacts on renal function. This study contributes valuable insights into the prognosis of AKI patients requiring dialysis. It underscores the need for further research on RFR as a diagnostic tool and the lasting consequences of AKI.

Proteinuria in predicting adverse outcomes in women with severe features of pre-eclampsia from a developing country: A prospective cohort study.

OBJECTIVE: To study the adverse maternal and perinatal outcomes in women with severe pre-eclampsia (SPE) among different ranges of proteinuria. METHODS: This prospective cohort study was conducted in Jawaharlal Institute of Postgraduate Medical Education and Research, India. After obtaining informed written consent, the 202 singleton women fulfilling the criteria of severe features of pre-eclampsia were stratified based on the value of urine protein-creatinine ratio (UPCR) as mild, moderate, severe, and massive proteinuria during pregnancy. Clinical outcomes were assessed and patients were followed up until 12 weeks postpartum to identify persistent proteinuria and hypertension. RESULTS: Of the 202 women with SPE, adverse maternal outcomes were seen in 34.65% (n = 70) and adverse perinatal outcomes in 75.74% (n = 153). The demographic and clinical factors were similar among women with increasing severity of proteinuria, except for mean systolic blood pressure, serum creatinine and total serum protein. UPCR was found to have a significant correlation with composite adverse perinatal outcome (P < 0.001) and individual outcomes of neonatal intensive care unit admission for >48 h (P = 0.01) and neonatal sepsis (P = 0.02) but not adverse maternal outcomes (P = 0.201). The optimum UPCR cutoff for adverse perinatal outcomes was 1.6 (sensitivity, 73.2%; specificity, 52.7%). In addition, 14.85% of the women had a persistently elevated UPCR and 3.96% had hypertension at 3 months postpartum. CONCLUSION: In women with SPE, severe and massive proteinuria were related to composite adverse perinatal outcome but not composite adverse maternal outcome. Moreover, antenatal 24-h proteinuria was significantly associated with persistent proteinuria. Significant proteinuria in women with SPE poses a risk for chronic renal dysfunction, requiring follow-up.

Potential Signature Therapeutic Biomarkers TOP2A, MAD2L1, and CDK1 in Colorectal Cancer: A Systems Biomedicine-Based Approach.

Colorectal cancer is the third deadliest and fourth most diagnosed cancer. It is heterogeneously driven by varied mutations and mutagens, and thus, it is challenging for targeted therapy. The rapid advancement of high-throughput technology presents considerable opportunities for discovering new colon cancer biomarkers. In the present study, we have explored and identified the biomarkers based on molecular interactions. We curated cancer datasets that were not micro-dissected and performed gene expression analysis. The protein-protein interactions were curated, and a network was constructed for the up-regulated genes. The hub genes were analyzed using 12 different topological parameters. The correlation analysis selected TOP2A, CDK1, CCNB1, AURKA, and MAD2L1 as hub genes. Further, survival analysis was performed to determine the effectiveness of the hub gene on the patient's survival rate. Our findings explore various transcription factors such as E2F4, FOXM1, E2F6, MAX, and SIN3A, along with kinases CSNK2A1, MAPK14, CDK1, CDK4, and CDK2, as potential molecular signatures and aid researchers in understanding the pathophysiological mechanisms underlying CRC development and thus providing novel therapeutic and diagnostic recourse. Furthermore, investigating miRNAs, we focused on hsa-miR-215-5p, hsa-miR-192-5p, and hsa-miR-193b-3p due to their observed impact on a diverse set of colorectal cancer genes. Thereby, the current approach brings into light CRC- related genes at the RNA and protein levels that can potentially act as novel biomarkers opening doors to diagnostic and treatment purposes.

Indian TrANslational GlomerulonephrItis BioLogy nEtwork (I-TANGIBLE): Design and Methods.

Background and Aim: Primary glomerular disease accounts for one-sixth of all chronic kidney diseases (CKDs) in India. We remain limited in our ability to effectively treat these conditions because of lack of understanding of the disease mechanisms and lack of predictors to identify the clinical course and therapeutic responsiveness. We propose to develop a network of investigators in glomerular diseases, collect information in a systematic fashion to understand the clinical outcomes, answer translational research questions better, and identify and recruit patients for clinical trials. Materials and Methods: This is a prospective, observational study. The Indian TrANslational GlomerulonephrItis BioLogy nEtwork (I-TANGIBLE) cohort will enroll patients (>18 years) with biopsy-proven minimal change disease (MCD), focal segmental glomerulonephritis (FSGS), membranous nephropathy (MN), IgA nephropathy (IgAN), or membranoproliferative glomerulonephritis (MPGN) (immune complex- and complement-mediated), with first biopsy taken within 2 years of enrollment. Patients with estimated glomerular filtration (eGFR) rate <15 ml/min/1.73 m2 for >3 months at the time of screening, kidney transplant or bone marrow transplant recipients, patients with active malignancy, and patients with active hepatitis B/C replication or human immunodeficiency virus (HIV)-I/II will be excluded. Clinical details including history, medication history and details, and family history will be obtained. Consenting patient's blood and urine samples will be collected and stored, aligned to their clinical follow-up. Expected Outcomes: The network will allow accurate ascertainment of disease burden of glomerular diseases across study sites, establishment of the treatment pattern of common glomerular diseases, investigation of medium- and long-term outcomes (remission, relapse, rate of eGFR decline), and building a suitable infrastructure to carry out clinical trials in primary glomerular disease.

Pan-genome and reverse vaccinology approaches to design multi-epitope vaccine against Epstein-Barr virus associated with colorectal cancer.

Epstein-Barr virus (EBV) is a global lymphotropic virus and has been associated with various malignancies, among which colorectal cancer (CRC) is the prevalent one causing mortality worldwide. In the recent past, numerous research efforts have been made to develop a potential vaccine against this virus; however, none is effective possibly due to their low throughput, laboriousness, and lack of sensitivity. In this study, we designed a multi-epitope subunit vaccine that targets latent membrane protein (LMP-2B) of EBV using pan-genome and reverse vaccinology approaches. Twenty-three major histocompatibility complex (MHC) epitopes (five class-I and eighteen class-II) and eight B-cell epitopes, which have been found to be antigenic, immunogenic, and non-toxic, were selected for the vaccine construction. Furthermore, 24 vaccine constructs (VCs) were designed from the predicted epitopes and out of which VC1 was selected and finalized based on its structural parameters. The functionality of VC1 was validated through molecular docking with different immune receptors (MHC class-I, MHC class-II, and TLRs). The binding affinity, molecular and immune simulation revealed that the VC1 had more stable interaction and is believed to elicit good immune responses against EBV. HIGHLIGHTS: Pan-genome and reverse vaccinology approaches were used to design a multi-epitope subunit vaccine against LMP-2B protein of EBV. Epitopes were selected based on the antigenic, immunogenic, and non-toxic properties. Twenty-four vaccine constructs (VCs) were designed from the predicted epitopes. Designed vaccine VC1 has shown good binding affinity and molecular and immune simulation. VC1 was validated using molecular docking with different immune receptors.

Network metrics, structural dynamics and density functional theory calculations identified a novel Ursodeoxycholic Acid derivative against therapeutic target Parkin for Parkinson's disease.

Parkinson's disease (PD) has been designated as one of the priority neurodegenerative disorders worldwide. Although diagnostic biomarkers have been identified, early onset detection and targeted therapy are still limited. An integrated systems and structural biology approach were adopted to identify therapeutic targets for PD. From a set of 49 PD associated genes, a densely connected interactome was constructed. Based on centrality indices, degree of interaction and functional enrichments, LRRK2, PARK2, PARK7, PINK1 and SNCA were identified as the hub-genes. PARK2 (Parkin) was finalized as a potent theranostic candidate marker due to its strong association (score > 0.99) with α-synuclein (SNCA), which directly regulates PD progression. Besides, modeling and validation of Parkin structure, an extensive virtual-screening revealed small (commercially available) inhibitors against Parkin. Molecule-258 (ZINC5022267) was selected as a potent candidate based on pharmacokinetic profiles, Density Functional Theory (DFT) energy calculations (ΔE = 6.93 eV) and high binding affinity (Binding energy = -6.57 ± 0.1 kcal/mol; Inhibition constant = 15.35 µM) against Parkin. Molecular dynamics simulation of protein-inhibitor complexes further strengthened the therapeutic propositions with stable trajectories (low structural fluctuations), hydrogen bonding patterns and interactive energies (>0kJ/mol). Our study encourages experimental validations of the novel drug candidate to prevent the auto-inhibition of Parkin mediated ubiquitination in PD.

A comprehensive review on genomics, systems biology and structural biology approaches for combating antimicrobial resistance in ESKAPE pathogens: computational tools and recent advancements.

In recent decades, antimicrobial resistance has been augmented as a global concern to public health owing to the global spread of multidrug-resistant strains from different ESKAPE pathogens. This alarming trend and the lack of new antibiotics with novel modes of action in the pipeline necessitate the development of non-antibiotic ways to treat illnesses caused by these isolates. In molecular biology, computational approaches have become crucial tools, particularly in one of the most challenging areas of multidrug resistance. The rapid advancements in bioinformatics have led to a plethora of computational approaches involving genomics, systems biology, and structural biology currently gaining momentum among molecular biologists since they can be useful and provide valuable information on the complex mechanisms of AMR research in ESKAPE pathogens. These computational approaches would be helpful in elucidating the AMR mechanisms, identifying important hub genes/proteins, and their promising targets together with their interactions with important drug targets, which is a crucial step in drug discovery. Therefore, the present review aims to provide holistic information on currently employed bioinformatic tools and their application in the discovery of multifunctional novel therapeutic drugs to combat the current problem of AMR in ESKAPE pathogens. The review also summarizes the recent advancement in the AMR research in ESKAPE pathogens utilizing the in silico approaches.

Myeloma Cast Nephropathy an Unusual Association with HIV Infection Presenting with Renal Dysfunction.

Human immunodeficiency virus (HIV)-associated renal disease is a pan-nephropathy, causing glomerular, tubular, and interstitial changes. The common lesion is the collapsing variant of focal segmental glomerulosclerosis. Multiple myeloma presenting as light chain cast nephropathy in an HIV-positive patient is very rare. A 45-year-old female retropositive patient presented with one episode of hematuria. Kidney biopsy was performed with a clinical diagnosis of acute interstitial nephritis (AIN). Biopsy showed unremarkable glomeruli. Tubules were dilated and showed a few periodic acid-Schiff (PAS) positive and many PAS-negative fractured casts surrounded by histiocytic reaction. Immunofluorescence and immunohistochemistry (IHC) showed lambda restriction by the casts. Bone marrow aspirate showed an increase in plasma cells, and the biopsy showed nodular aggregates of atypical plasma cells, which showed lambda restriction by IHC. PAS-negative fractured tubular casts are known to be associated with HIV-related nephropathy and need detailed hematological workup to rule out an associated plasma cell dyscrasia.

Characteristics and Outcome of Biopsy-proven Malignant Hypertension with Severe Kidney Injury: A Retrospective Study.

BACKGROUND: Although malignant hypertension begets multiple target organ damage, there is limited data on patients with severe renal injury and evident malignant hypertension in renal histopathology. METHODS: We assessed the baseline demographic, histopathological findings and clinical outcomes in this retrospective analysis of patients with biopsy-proven malignant hypertension. RESULTS: Thirty cases were analysed, the mean age of patients was 40 ± 11.5 years, 28 (93.3%) were males and the average systolic and diastolic blood pressures at hospitalisation were 197.04 ± 24.14 and 117.41 ± 18.31 mmHg, respectively. Severe retinopathy was seen in 10 (33.3%). The median eGFR at admission was 6.3 (IQR 4.4-9.15) mL/min and 21 (72.4%) needed dialysis. Nine (30%) cases with glomerular crescents were having the primary glomerular disease (7 IgAN, 1 C3 glomerulonephritis, 1 membranoproliferative glomerulonephritis) and 17 (56.6%) had thrombotic microangiopathy. Three-month ESRD free survival was 34.5% (n = 10) and the ESRD cohort had more incidence of dialysis requiring kidney injury at presentation (94.4% vs. 40% in the non-ESRD cohort). Patient survival at 1 year was 50%. Isolated malignant hypertension, differed from others with regard to lesser incidence of severe retinopathy, less glomerular sclerosis (29.61 ± 15.86 vs. 48.45% ± 30.78; P = 0.03), absence of crescents (P = 0.02), more incidence of tuft wrinkling (100% vs. 35%, P = 0.00) and total vessel occlusion (P = 0.02). CONCLUSION: Clinicopathologically, accelerated essential hypertension differs from hypertension of glomerular disease. Degree of kidney injury at presentation is risk predictor for long-term morbidity in malignant hypertension.

Cholemic Nephrosis: An Autopsy Study of a Forgotten Entity.

OBJECTIVE: The aim of the study is to do a clinicopathologic study of post mortem kidney biopsies with significant deposition of bilirubin pigment within tubular epithelial cells and in the lumen of distal tubules as a bile cast. MATERIAL AND METHOD: All post mortem specimens with acute tubular necrosis, with the presence of bile casts in tubules or bile pigment deposition in the tubular epithelium during the period 2015-2018 were examined for gross and histopathology along with biochemical parameters and viral markers. RESULTS: Bile casts with sloughed renal tubular epithelial cells and occasional macrophages were present in the distal convoluted tubule in 78.6% of biopsies (11/14). The plugging of distal convoluted tubule with casts was similar to that seen in myeloma and myoglobin cast nephropathies. Bilirubin pigment deposition was present in 35.7% (5/14) of cases. The frequency of bile casts in each biopsy was variable and it did not have any association with serum bilirubin levels or etiology of liver dysfunction. A striking difference from earlier studies is the high number of toxin-induced liver damage including six cases of paraquat and 2 cases of yellow phosphorus poisoning. CONCLUSION: This study proves importance of the bile cast nephropathy as a reason for kidney injury, especially with varied hepatotoxic etiologies, especially paraquat and yellow phosphorus.

Role of Urinary Beta 2 Microglobulin and Kidney Injury Molecule-1 in Predicting Kidney Function at One Year Following Acute Kidney Injury.

BACKGROUND: There is only limited information on the utility of urinary biomarkers in predicting long-term kidney function following acute kidney injury (AKI). The current study assessed whether urinary beta 2 microglobulin/creatinine (B2M/creat) and kidney injury molecule-1/creatinine (KIM-1/creat) ratios, measured in the early recovery phase of AKI, are predictive of kidney function at one year. METHODS: This is a prospective study done in a tertiary care centre in South India, from March 2017 to December 2018. Adult patients who survived an episode of AKI were followed up for one year (n=125). B2M/creat and KIM-1/creat ratio were measured at two weeks and three months following AKI. RESULTS: In the AKI survivors, the B2M/creat ratio at 2 weeks [18.3mg/g (IQR 2.3, 52.9)] and KIM-1/creat ratio [1.1 µg/g (IQR 0.5, 4.0) at two weeks were higher compared to healthy controls [B2M/creat ratio 0.35 mg/g (0.17,0.58) and KIM-1/creat ratio 0.40 µg/g (0.23,1.00); P=<0.001]. After adjusting for covariates, the eGFR and urinary B2M/creat ratio at two weeks following AKI were predictive of eGFR at one year (P<0.001). KIM-1/ creat ratios were not predictive of eGFR at one year. A urinary B2M/creat ratio of 10.85 at two weeks following AKI had an 85.5% sensitivity (95% CI 74, 93) and 64.3% (95% CI 53, 75) specificity to predict CKD at one year. An eGFR cutoff of 60 mL/min/1.73 m2 at two weeks had a sensitivity of 81.8% (95% CI 69, 90) and specificity of 71.4% (95% CI 60, 81) for predicting CKD. The presence of either one criteria (urinary B2M/creat ratio >10.85 (mg/g) or eGFR <60 mL at two weeks) had a sensitivity of 100% (95% CI 94%, 100%) in predicting CKD at one year. CONCLUSION: An eGFR <60 mL/min/1.73m2 and elevated urinary B2M/creat ratio at two weeks following AKI is predictive of low eGFR at one year. Urinary KIM-1/creat ratios do not predict CKD progression.

Erratum: Prognosis and long-term outcomes of acute kidney injury due to snake envenomation.

[This corrects the article DOI: 10.1093/ckj/sfz055.][This corrects the article DOI: 10.1093/ckj/sfz055.].

Prognosis and long-term outcomes of acute kidney injury due to snake envenomation.

BACKGROUND: Snakebite is a common occupational hazard in tropical countries. To date, the literature on snakebite-related acute kidney injury (AKI) has been limited by retrospective study designs, lack of uniformity in case definitions of AKI and limited follow-up. This study aims to identify the in-hospital outcomes and long-term changes in kidney function that follow haemotoxic envenomation. METHODS: All adult patients admitted with AKI following haemotoxic envenomation from January 2016 to June 2017 were recruited and followed up until July 2018. Predictors of in-hospital mortality was assessed. Long-term follow-up data on kidney function were collected from survivors. RESULTS: In total, 184 patients with haemotoxic envenomation and AKI were recruited. The mean age of the subjects was 42.2 years [95% confidence interval (CI) 40.3-44.7]. The majority were male (71.2%). The mortality of patients with haemotoxic envenomation was 21.5%. The mortality was considerably higher in patients with Kidney Disease: Improving Global Outcomes (KDIGO) Stage 3 AKI [relative risk (RR) 4.45 (95% CI 1.14-17.42)] and those who met KDIGO urine output criteria [RR 20.45 (95% CI 2.84-147.23)]. A Cox regression model identified mechanical ventilation [odds ratio (OR) 5.59 (95% CI 2.90-10.81)], hypotension [OR 2.48 (95% CI 1.31-4.72)] and capillary leak syndrome [OR 2.02 (95% CI 1.05-3.88)] as independent predictors of mortality. Long-term follow-up data were available for 73 patients. A total of 21 patients (28.7%) developed adverse renal outcomes (glomerular filtration rate <60 mL/min/1.73 m2, urine albumin excretion >30 mg/g and new-onset hypertension or prehypertension). CONCLUSIONS: AKI resulting from snake envenomation is associated with considerable risk of mortality. The greater the AKI stage the greater the likelihood of mortality. One-third of patients with AKI developed long-term complications like chronic kidney disease, prehypertension and hypertension over the follow-up period.