Targeted-Neuroinflammation Mitigation Using Inflammasome-Inhibiting Nanoligomers is Therapeutic in an Experimental Autoimmune Encephalomyelitis Mouse Model.

Multiple sclerosis (MS) is a debilitating autoimmune disease that impacts millions of patients worldwide, disproportionately impacting women (4:1), and often presenting at highly productive stages of life. This disease affects the spinal cord and brain and is characterized by severe neuroinflammation, demyelination, and subsequent neuronal damage, resulting in symptoms like loss of mobility. While untargeted and pan-immunosuppressive therapies have proven to be disease-modifying and manage (or prolong the time between) symptoms in many patients, a significant fraction are unable to achieve remission. Recent work has suggested that targeted neuroinflammation mitigation through selective inflammasome inhibition can offer relief to patients while preserving key components of immune function. Here, we show a screening of potential therapeutic targets using inflammasome-inhibiting Nanoligomers (NF-κB1, TNFR1, TNF-α, IL-6) that meet or far-exceed commercially available small-molecule counterparts like ruxolitinib, MCC950, and deucravacitinib. Using the human brain organoid model, top Nanoligomer combinations (NF-κB1 + TNFR1: NI111, and NF-κB1 + NLRP3: NI112) were shown to significantly reduce neuroinflammation without any observable negative impact on organoid function. Further testing of these top Nanoligomer combinations in an aggressive experimental autoimmune encephalomyelitis (EAE) mouse model for MS using intraperitoneal (IP) injections showed that NF-κB1 and NLRP3 targeting Nanoligomer combination NI112 rescues mice without observable loss of mobility or disability, minimal inflammation in brain and spinal cord histology, and minimal to no immune cell infiltration of the spinal cord and no demyelination, similar to or at par with mice that received no EAE injections (negative control). Mice receiving NI111 (NF-κB1 + TNFR1) also showed reduced neuroinflammation compared to saline (sham)-treated EAE mice and at par/similar to other inflammasome-inhibiting small molecule treatments, although it was significantly higher than NI112 leading to subsequent worsening clinical outcomes. Furthermore, treatment with an oral formulation of NI112 at lower doses showed a significant reduction in EAE severity, albeit with higher variance owing to administration and formulation/fill-and-finish variability. Overall, these results point to the potential of further development and testing of these inflammasome-targeting Nanoliogmers as an effective neuroinflammation treatment for multiple neurodegenerative diseases and potentially benefit several patients suffering from such debilitating autoimmune diseases like MS.

Emerging Role of Autophagy in Governing Cellular Dormancy, Metabolic Functions, and Therapeutic Responses of Cancer Stem Cells.

Tumors are composed of heterogeneous populations of dysregulated cells that grow in specialized niches that support their growth and maintain their properties. Tumor heterogeneity and metastasis are among the major hindrances that exist while treating cancer patients, leading to poor clinical outcomes. Although the factors that determine tumor complexity remain largely unknown, several genotypic and phenotypic changes, including DNA mutations and metabolic reprograming provide cancer cells with a survival advantage over host cells and resistance to therapeutics. Furthermore, the presence of a specific population of cells within the tumor mass, commonly known as cancer stem cells (CSCs), is thought to initiate tumor formation, maintenance, resistance, and recurrence. Therefore, these CSCs have been investigated in detail recently as potential targets to treat cancer and prevent recurrence. Understanding the molecular mechanisms involved in CSC proliferation, self-renewal, and dormancy may provide important clues for developing effective therapeutic strategies. Autophagy, a catabolic process, has long been recognized to regulate various physiological and pathological processes. In addition to regulating cancer cells, recent studies have identified a critical role for autophagy in regulating CSC functions. Autophagy is activated under various adverse conditions and promotes cellular maintenance, survival, and even cell death. Thus, it is intriguing to address whether autophagy promotes or inhibits CSC functions and whether autophagy modulation can be used to regulate CSC functions, either alone or in combination. This review describes the roles of autophagy in the regulation of metabolic functions, proliferation and quiescence of CSCs, and its role during therapeutic stress. The review further highlights the autophagy-associated pathways that could be used to regulate CSCs. Overall, the present review will help to rationalize various translational approaches that involve autophagy-mediated modulation of CSCs in controlling cancer progression, metastasis, and recurrence.

Comparative study of the effects of laser peripheral iridotomy and cataract surgery on anterior chamber angle parameters in primary angle closure suspect patients.

INTRODUCTION: Prophylactic laser peripheral iridotomy (LPI) and cataract surgery are considered the primary treatments for primary angle closure suspect (PACS) as they have proven effectiveness in widening the iridocorneal angle and addressing the underlying anatomical issues associated with this condition. The objective of this study is to compare the impact of LPI and cataract surgery on anterior chamber angle parameters, aiming to fill the existing research gap. METHODOLOGY: A prospective comparative study was conducted, involving 76 eyes of 61 patients. The study focused on patients diagnosed with PACSs and early cataract. The patients received treatment either through LPI or cataract surgery. Comprehensive eye examination was performed, including gonioscopy and anterior segment parameters were measured using anterior segment ocular coherence tomography (ASOCT). Follow-up examinations were conducted at 1 week and 1 month after the procedures, which included ASOCT and gonioscopy performed during the 1-month follow-up. RESULTS: All anterior chamber angle parameters increased significantly after treatment in both groups, including trabecular iris angle (TIA), angle opening distance at 250, 500 and 750 µm (AOD 250, AOD500, AOD750), trabecular iris surface area at 500 and 750 µm (TISA500, TISA750) and angle recess area at 500 and 750 µm from scleral spur (ARA500, ARA750) (p<0.05 for all). Moreover, all these parameters were greater after cataract surgery than after LPI (p<0.05 for all). CONCLUSION: Compared with LPI, cataract extraction resulted in a wider anterior chamber angle. Moreover, no residual angle closure was observed after cataract extraction, which could morphologically prevent the progress of angle closure. Thus, cataract extraction is superior to LPI in PACSs with early cataract in widening the anterior chamber angle.

The second wave of COVID-19 wreaked havoc: A look at clinical and laboratory parameters of survivors and non-survivors admitted to Intensive Care Unit, a single-centered retrospective study.

Background: The second wave of COVID-19 was disastrous and claimed many lives in India and abroad. The most challenging task was to provide the required treatment as per the patient's condition, within a limited span of time. The lack of prognostic predictors at the time of admission led to failure in prioritizing the patient's need for intensive care. Aim: This study was conducted to find out the clinical and laboratory parameters at the time of admission to ICU as predictors of outcomes in COVID-19 patients, which can help in judicious utilization of the available resources for better patient care. Subjects and Methods: Study comprises of 161 ICU admitted patients. Study of clinical traits, comorbidities, test results, and demographic variables were carried out among survivors and non-survivor. Result: Maximum death were patients of age group 21-30 years and male gender. Mortality in hypertensives, diabetics, and patients with sepsis were found to be statistically significant. Patients who developed ARDS and pneumonia or needed ventilation died invariably. High levels of laboratory parameters like IL-6, LDH, PT, INR, aPTT, ferritin, WBC count, and D-dimer were significantly associated with poor outcomes and at a particular cutoff had optimum sensitivity and specificity to predict mortality in ICU admitted COVID-19 patients. At the same time, low lymphocyte count and PaO2/FiO2 ratio was significantly associated with bad prognosis (P < 0.05). Conclusion: This paper will help in prioritizing patients in ICU who need special attention especially at the time of meager supply of resources.

Rise of biologics in noninfectious uveitis: a retrospective cohort study from Nepal.

Uveitis is a sight-threatening disease that poses a heavy burden on the quality of life. The treatment of uveitis has been revolutionized in the past two decades. Most remarkable among these is the emergence of biologics, which have shown to be effective and safer therapeutic option in noninfectious uveitis. Biologics are very useful when conventional immunomodulator therapy has failed or has been poorly tolerated. The most widely used biologics are tumor necrosis factor-α inhibitors (infliximab and adalimumab) with promising results. Other drugs include anti-CD20 inhibitors (rituximab), interleukin-6R-inhibitor (tocilizumab), interleukin-1R-inhibitor (anakinra), and Janus-associated kinase inhibitor (tofacitinib). Methods: A retrospective review of all cases of noninfectious uveitis and scleritis presenting to our center from July 2019 to January 2021 and had been treated with biological therapy were included. Results: We included 12 eyes of 10 patients. The mean age was 42.10±9.71 years. Anterior nongranulomatous uveitis comprised 70% of the cases and the most common etiology of anterior uveitis was spondyloarthritis (seven cases among which five cases were nonradiographic) axial spondyloarthritis (human leukocyte antigen B27 positive) followed by radiographic axial spondyloarthritis (two cases). The first line of treatment in all cases was conventional synthetic disease-modifying antirheumatic agents among which 50% (n=5) had received methotrexate (≥15 mg/week). As a second line of treatment, one or more biologics was used. Majority of the patients received oral tofacitinib 50% (n=5) followed by Inj adalimumab 30% (n=3). One case of Behcet's disease required sequential biologics (Inj adalimumab followed by oral tofacitinib). All patients tolerated and responded well to the treatment and no recurrences were observed after discontinuation of biologics drugs during the follow-up period of 1 year. Conclusion: Biologics are a relatively safe and effective modality of treatment in refractory, recurrent noninfectious uveitis.

A case of oculocutaneous sarcoidosis.

Purpose: To present a case of extrapulmonary sarcoidosis presenting with ocular and cutaneous involvement. Observations: We report a 54-year-male who presented with bilateral redness of eyes, photophobia, and diminished vision for a week. The best corrected visual acuity in the right eye was 6/60 and the left eye was counting fingers close to face (CFCF). He also had multiple brown plaques on the nape of the neck, chest, back, and arms. Furthermore, he was on multiple antipsychotic drugs for schizophrenia for 3 years. Uveitis investigation workup revealed raised serum angiotensin converting enzyme (ACE), negative Mantoux, and other serological tests. The patient was treated for acute anterior uveitis secondary to sarcoidosis. Clinical improvement was seen after a few days following treatment. The patient presented a year later with multiple yellowish conjunctival nodules in the superior bulbar conjunctiva associated with hyperemia. A biopsy of the plaque like skin lesions was done, which suggested cutaneous sarcoidosis. Involvement of the skin and the eyes raised suspicion that the persistent psychotic episodes despite multiple antipsychotic drugs could be attributed to neurosarcoidosis. However, magnetic Resonance Imaging (MRI) of the brain and orbit showed normal findings. After treatment with corticosteroids and immunosuppressives (methotrexate), the conjunctival nodules as well as skin lesions drastically improved, and the psychosis also responded well to clozapine. Conclusion: A high index of suspicion is needed in cases presenting with granulomatous uveitis with multisystem involvement. Long-term follow-up is crucial to monitor the disease progression and adverse effects of medications.

Piperine analog PGP-41 treatment overcomes paclitaxel resistance in NCI/ADR-RES ovarian cells by inhibition of MDR1.

Chemoresistance is one of the leading causes of the failure of chemotherapy. Overexpression of P-glycoprotein (P-gp) in cancer cells is one of the most important contributing factors toward the development of chemoresistance. This study was designed to synthesize the derivatives of dihydronaphthyl and to evaluate the P-gp inhibition activity of these compounds. Among all the compounds, PGP-41 showed the most potent P-gp inhibition activity in colorectal adenocarcinoma LS-180 cells. This compound showed potent P-gp inhibition activity in chemoresistant ovarian cell line NCI/ADR-RES. Paclitaxel is one of the first lines of drugs for treating ovarian cancer and is a substrate of P-gp; therefore, NCI/ADR-RES cells are highly resistant to treatment with paclitaxel. Based on this information, we evaluated PGP-41 to overcome the paclitaxel resistance of NCI/ADR-RES cells. PGP-41 was able to sensitize the NCI/ADR-RES cells to the treatment of paclitaxel, which was evident by the reduced IC50 value of paclitaxel from 6.64 µM to 0.12 µM. The sensitization of NCI/ADR-RES cells by PGP-41 was comparable to that of elacridar and Zosuquidar. Further studies revealed that the PGP-41 exerts its effect by downregulating the expression of P-gp. Reduction of P-gp activity leads to the accumulation of higher intracellular concentration of paclitaxel, and thus allowing it to interact with its targets, which further helps in its increased efficacy. Paclitaxel was able to arrest the sensitized NCI/ADR-RES cells into G2M phase, which ultimately led to the induction of apoptotic proteins and the death of cancer cells. Being a different scaffold from zosuquidar and elacridar, further studies are required to develop PGP-41 into a potential drug to overcome chemoresistance in cancer cells.

Role of multimodal imaging in differentiating unilateral APMPPE from unilateral Harada disease - a case report.

Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is classified as a part of the spectrum of the white dot syndromes affecting the inner choroid and the outer retina. It is usually bilateral and affects young patients between the second and fourth decades. The authors report an unusual case of unilateral APMPPE mimicking Vogt-Koyanagi-Harada (VKH) disease where the fundus fluorescein angiography was instrumental in confirming the diagnosis. Case presentation: A 35-year-old male presented with decreased visual acuity in the right eye for 3 days. Fundus examination revealed minimal vitritis, disc edema, and multifocal yellowish placoid lesions. Optical coherence tomography (OCT) showed the accumulation of subretinal fluid with subretinal septations closely mimicking VKH. Fundus fluorescein angiography depicted features of early hypofluorescence and late staining of the placoid lesions, suggesting APMPPE. Subretinal fluid partly resolved within a week, and visual acuity improved to 6/9(20/30) in the affected eye after the use of oral NSAIDS. Complete resolution of subretinal fluid was seen after 6 weeks. Clinical discussion: The most distinguishing feature in this case is the unilateral presentation and macular serous retinal detachment with subretinal septa on OCT imaging, which are not the typical features in APMPPE but quite similar to the characteristic features in acute VKH disease. Conclusion: APMPPE and acute VKH disease may share some overlapping clinical manifestations and imaging findings on OCT. APMPPE is a self-resolving disease, unlike VKH, and early diagnosis can avoid unnecessary administration of steroids and related side effects.

Surgeries and Outcomes in Subluxated and Dislocated Lens in Eastern Nepal.

INTRODUCTION: Many ocular or systemic conditions can cause weakening of the zonules, leading to subluxation or complete dislocation of lens into the anterior chamber or vitreous cavity. OBJECTIVES: To evaluate the outcome of surgery in cases with subluxated and dislocated lens. MATERIALS AND METHODS: Retrospective chart review of all cases with subluxated and dislocated lens who underwent surgery in a one-year period from 2019 January to 2019 December was conducted. Demographic profile, systemic comorbidities, initial and final best corrected visual acuity (BCVA), surgical procedure were recorded along with all the intraoperative and post-operative complications. RESULTS: A total of 62 eyes of 60 patients with mean age of 50.18 ± 15.18 years (18 to 87 years) were included with the modal duration of presentation of one week. Among these, trauma was found to be the most common etiology. Subluxation was present in 55 eyes and seven eyes had dislocation. Intracapsular Cataract Extraction (ICCE) was performed in 41 while 21 underwent Extracapsular Cataract Extraction (ECCE); and surgical intervention elicited a statistically significant (p < 0.05) improvement in the visual acuity. The BCVA was statistically better among the pseudophakic patient. Most common complication encountered intraoperatively was vitreous loss and post operatively was significant corneal edema. CONCLUSION: Cataract extraction in cases with subluxated and dislocated lens due to different etiology results in the improvement in the visual acuity of the patient. In cases where ECCE cannot be performed, ICCE also results in comparable visual improvement.

Changes in Central Corneal Thickness and Central Macular Thickness following Uncomplicated Small-incision Cataract Surgery.

INTRODUCTION: Cataract surgery is an invasive procedure that causes mechanical and inflammatory insult to the eye. OBJECTIVES: The objective was to study the changes in central corneal thickness (CCT) which is an indirect indicator of corneal endothelial dysfunction and the changes in macular thickness following uncomplicated small incision cataract surgery (SICS) Materials and methods: This was a prospective observational study with a before-and-after design conducted in Reiyukai Eiko Masunaga eye hospital, Banepa, Kavrepalanchok, Nepal. SICS was performed on 68 eyes of 62 patients. Change in CCT and central macular thickness (CMT) from baseline was observed post-surgery on the first day, one week, and six weeks. RESULTS: There were 27 (43.5%) females and 35 males (56.5%) in the study. Mean age was 58.26 ±10 years. This difference of visual acuity between pre and post-operative state was statistically significant. The first post-operative day (POD) and first week post-operative CCT values when compared with preoperative CCT values were statistically significant. However, post-operative CCT values at six weeks were similar to preoperative values. Also, the differences at day one, first week and six weeks post-operative CMT values when compared with preoperative CMT values were statistically significant. CONCLUSION: This study revealed that there is a significant rise in CCT after SICS which gradually tends to normalize at six weeks. Similarly there is a gradual rise in CMT after SICS persisting even at six weeks. These changes were subtle and there was a marked improvement of visual acuity at six weeks after SICS.

Looking on the horizon; potential and unique approaches to developing radiation countermeasures for deep space travel.

Future lunar missions and beyond will require new and innovative approaches to radiation countermeasures. The Translational Research Institute for Space Health (TRISH) is focused on identifying and supporting unique approaches to reduce risks to human health and performance on future missions beyond low Earth orbit. This paper will describe three funded and complementary avenues for reducing the risk to humans from radiation exposure experienced in deep space. The first focus is on identifying new therapeutic targets to reduce the damaging effects of radiation by focusing on high throughput genetic screens in accessible, sometimes called lower, organism models. The second focus is to design innovative approaches for countermeasure development with special attention to nucleotide-based methodologies that may constitute a more agile way to design therapeutics. The final focus is to develop new and innovative ways to test radiation countermeasures in a human model system. While animal studies continue to be beneficial in the study of space radiation, they can have imperfect translation to humans. The use of three-dimensional (3D) complex in vitro models is a promising approach to aid the development of new countermeasures and personalized assessments of radiation risks. These three distinct and unique approaches complement traditional space radiation efforts and should provide future space explorers with more options to safeguard their short and long-term health.

Reversing radiation-induced immunosuppression using a new therapeutic modality.

Radiation-induced immune suppression poses significant health challenges for millions of patients undergoing cancer chemotherapy and radiotherapy treatment, and astronauts and space tourists travelling to outer space. While a limited number of recombinant protein therapies, such a Sargramostim, are approved for accelerating hematologic recovery, the pronounced role of granulocyte-macrophage colony-stimulating factor (GM-CSF or CSF2) as a proinflammatory cytokine poses additional challenges in creating immune dysfunction towards pathogenic autoimmune diseases. Here we present an approach to high-throughput drug-discovery, target validation, and lead molecule identification using nucleic acid-based molecules. These Nanoligomer™ molecules are rationally designed using a bioinformatics and an artificial intelligence (AI)-based ranking method and synthesized as a single-modality combining 6-different design elements to up- or downregulate gene expression of target gene, resulting in elevated or diminished protein expression of intended target. This method additionally alters related gene network targets ultimately resulting in pathway modulation. This approach was used to perturb and identify the most effective upstream regulators and canonical pathways for therapeutic intervention to reverse radiation-induced immunosuppression. The lead Nanoligomer™ identified in a screen of human donor derived peripheral blood mononuclear cells (PBMCs) upregulated Erythropoietin (EPO) and showed the greatest reversal of radiation induced cytokine changes. It was further tested in vivo in a mouse radiation-model with low-dose (3 mg/kg) intraperitoneal administration and was shown to regulate gene expression of epo in lung tissue as well as counter immune suppression. These results point to the broader applicability of our approach towards drug-discovery, and potential for further investigation of our lead molecule as reversible gene therapy to treat adverse health outcomes induced by radiation exposure.

Identifying an Optimal Neuroinflammation Treatment Using a Nanoligomer Discovery Engine.

Acute activation of innate immune response in the brain, or neuroinflammation, protects this vital organ from a range of external pathogens and promotes healing after traumatic brain injury. However, chronic neuroinflammation leading to the activation of immune cells like microglia and astrocytes causes damage to the nervous tissue, and it is causally linked to a range of neurodegenerative diseases such as Alzheimer's diseases (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), and many others. While neuroinflammation is a key target for a range of neuropathological diseases, there is a lack of effective countermeasures to tackle it, and existing experimental therapies require fairly invasive intracerebral and intrathecal delivery due to difficulty associated with the therapeutic crossover between the blood-brain barrier, making such treatments impractical to treat neuroinflammation long-term. Here, we present the development of an optimal neurotherapeutic using our Nanoligomer Discovery Engine, by screening downregulation of several proinflammatory cytokines (e.g., Interleukin-1ß or IL-1ß, tumor necrosis factor-alpha or TNF-α, TNF receptor 1 or TNFR1, Interleukin 6 or IL-6), inflammasomes (e.g., NLRP1), key transcription factors (e.g., nuclear factor kappa-B or NF-κß) and their combinations, as upstream regulators and canonical pathway targets, to identify and validate the best-in-class treatment. Using our high-throughput drug discovery, target validation, and lead molecule identification via a bioinformatics and artificial intelligence-based ranking method to design sequence-specific peptide molecules to up- or downregulate gene expression of the targeted gene at will, we used our discovery engine to perturb and identify most effective upstream regulators and canonical pathways for therapeutic intervention to reverse neuroinflammation. The lead neurotherapeutic was a combination of Nanoligomers targeted to NF-κß (SB.201.17D.8_NF-κß1) and TNFR1 (SB.201.18D.6_TNFR1), which were identified using in vitro cell-based screening in donor-derived human astrocytes and further validated in vivo using a mouse model of lipopolysaccharide (LPS)-induced neuroinflammation. The combination treatment SB_NI_111 was delivered without any special formulation using a simple intraperitoneal injection of low dose (5 mg/kg) and was found to significantly suppress the expression of LPS-induced neuroinflammation in mouse hippocampus. These results point to the broader applicability of this approach towards the development of therapies for chronic neuroinflammation-linked neurodegenerative diseases, sleep countermeasures, and others, and the potential for further investigation of the lead neurotherapeutic molecule as reversible gene therapy.

The effects of prostaglandin E2 on gene expression of IDG-SW3-derived osteocytes in 2D and 3D culture.

Prostaglandin E2 (PGE2) is a key signaling molecule produced by osteocytes in response to mechanical loading, but its effect on osteocytes is less understood. This work examined the effect of PGE2 on IDG-SW3-derived osteocytes in standard 2D culture (collagen-coated tissue culture polystyrene) and in a 3D degradable poly(ethylene glycol) hydrogel. IDG-SW3 cells were differentiated for 35 days into osteocytes in 2D and 3D cultures. 3D culture led to a more mature osteocyte phenotype with 100-fold higher Sost expression. IDG-SW3-derived osteocytes were treated with PGE2 and assessed for expression of genes involved in PGE2, anabolic, and catabolic signaling. In 2D, PGE2 had a rapid (1 h) and sustained (24 h) effect on many PGE2 signaling genes, a rapid stimulatory effect on Il6, and a sustained inhibitory effect on Tnfrsf11b and Bglap. Comparing culture environment without PGE2, osteocytes had higher expression of all four EP receptors and Sost but lower expression of Tnfrsf11b, Bglap, and Gja1 in 3D. Osteocytes were more responsive to PGE2 in 3D. With increasing PGE2, 3D led to increased Gja1 and decreased Sost expressions and a higher Tnfrsf11b/Tnfsf11 ratio, indicating an anabolic response. Further analysis in 3D revealed that EP4, the receptor implicated in PGE2 signaling in bone, was not responsible for the PGE2-induced gene expression changes in osteocytes. In summary, osteocytes are highly responsive to PGE2 when cultured in an in vitro 3D hydrogel model suggesting that autocrine and paracrine PGE2 signaling in osteocytes may play a role in bone homeostasis.

Optical coherence tomography patterns of diabetic macular edema and treatment response to bevacizumab: a short-term study.

Background: The purpose of this study was to evaluate the short-term response of intravitreal bevacizumab in diabetic macular edema (DME) and assess the variation in treatment outcomes in different morphology patterns using spectral domain-optical coherence tomography (SD-OCT). Objective: To study different morphological patterns of DME based on OCT and compare their treatment response to bevacizumab. Methods: Hundred and twelve eyes of 112 patients with DME were included and treated with intravitreal bevacizumab (1.25 mg/0.05 ml monthly for 3 months). The morphological patterns of DME were classified on the basis of OCT into three groups - diffuse retinal thickening (DRT), cystoid macular edema (CME), and serous retinal detachment (SRD) - and changes in central macular thickness (CMT) and best corrected visual acuity (BCVA) after treatment were compared. Results: A total of 112 eyes with DME were included and consisted of 40 DRT, 37 CME, and 35 SRD. Treatment with bevacizumab resulted in decrease in central macular thickness and improvement in BCVA in all three groups. The baseline visual acuity and CMT of DRT group was better than that of the other two groups. The treatment outcome was measured in terms of CMT and BCVA. Change in CMT was statistically significant among three groups and was found to be better in DRT group (p < 0.05, 95% confidence interval). However, there was statistically no significant variation between the three groups regarding the change in BCVA (p = 0.169, 95% confidence interval). Conclusion: Anatomic and visual improvement can be achieved by bevacizumab in all patterns of DME. However, individual pattern may respond differently. DRT, which appears to be the earliest form of DME, responds better than other types. Thus, the pattern of macular edema shown by OCT may provide an objective guideline in predicting the response of bevacizumab injection in DME.

Facilitating Safe Discharge Through Predicting Disease Progression in Moderate Coronavirus Disease 2019 (COVID-19): A Prospective Cohort Study to Develop and Validate a Clinical Prediction Model in Resource-Limited Settings.

BACKGROUND: In locations where few people have received coronavirus disease 2019 (COVID-19) vaccines, health systems remain vulnerable to surges in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Tools to identify patients suitable for community-based management are urgently needed. METHODS: We prospectively recruited adults presenting to 2 hospitals in India with moderate symptoms of laboratory-confirmed COVID-19 to develop and validate a clinical prediction model to rule out progression to supplemental oxygen requirement. The primary outcome was defined as any of the following: SpO2 < 94%; respiratory rate > 30 BPM; SpO2/FiO2 < 400; or death. We specified a priori that each model would contain three clinical parameters (age, sex, and SpO2) and 1 of 7 shortlisted biochemical biomarkers measurable using commercially available rapid tests (C-reactive protein [CRP], D-dimer, interleukin 6 [IL-6], neutrophil-to-lymphocyte ratio [NLR], procalcitonin [PCT], soluble triggering receptor expressed on myeloid cell-1 [sTREM-1], or soluble urokinase plasminogen activator receptor [suPAR]), to ensure the models would be suitable for resource-limited settings. We evaluated discrimination, calibration, and clinical utility of the models in a held-out temporal external validation cohort. RESULTS: In total, 426 participants were recruited, of whom 89 (21.0%) met the primary outcome; 257 participants comprised the development cohort, and 166 comprised the validation cohort. The 3 models containing NLR, suPAR, or IL-6 demonstrated promising discrimination (c-statistics: 0.72-0.74) and calibration (calibration slopes: 1.01-1.05) in the validation cohort and provided greater utility than a model containing the clinical parameters alone. CONCLUSIONS: We present 3 clinical prediction models that could help clinicians identify patients with moderate COVID-19 suitable for community-based management. The models are readily implementable and of particular relevance for locations with limited resources.

Efficacy of Lipid Ratios and Platelet Distribution Width for Assessment of Liver Fibrosis in Patients With Non-alcoholic Fatty Liver Disease.

Introduction The clinical course of non-alcoholic fatty liver disease (NAFLD) in its long term may follow a benign course or have an adverse outcome leading to hepatocellular carcinoma (HCC) or end-stage liver disease requiring liver transplantation. Such patients represent only a small proportion of all NAFLD cases, making case finding a real challenge. Aims This study was planned to test the efficacy of simple laboratory parameters for their ability to screen advanced cases of NAFLD who need early attention to extricate them from the cumbersome outcome. Material and method The study protocol enrolled 129 diagnosed cases of NAFLD. Patients were categorized as group I with mild/moderate fibrosis (MF) comprising of F0 to F2 and group II with advanced fibrosis (AF) comprising of F3 and F4 based on Fibroscan kPa (kilopascal) score. Results Group I consisted of 96 MF patients, while group II included 33 AF patients. Mean values of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), triglyceride (TG), triglyceride/high-density lipoprotein (TG/HDL) ratio, total cholesterol/high-density lipoprotein (TC/HDL) ratio, and platelet distribution width (PDW) were significantly higher in patients with AF (group II), while platelet count (PC) was significantly lower in group II. The area under the receiver operative characteristic (AUROC) curve was highest for PDW [0.730 (0.644-0.815)] and TG/HDL ratio [0.719 (0.612-0.827)]. TG/HDL ratio at a cut-off of >2.4 had a sensitivity and specificity of 84.85% and 34.38%, respectively, and PDW at a cut-off of >16.40 had a sensitivity and specificity of 84.85% and 54.17%, respectively. Conclusion Decent sensitivity at particular cut-offs for TG/HDL ratio and PDW makes them suitable to be applied for screening advanced cases of NAFLD that require early ministration and medication to block its further progression to its intricate form.

Prevalence and Etiological Profile of Hypercalcemia in Hospitalized Adult Patients and Association with Mortality.

Background: The etiology of hypercalcemia varies according to the clinical setting. Hitherto, data on the prevalence and profile of hypercalcemia in hospitalized Asian-Indian patients are limited. Hence, we conducted a prospective observational study to determine the prevalence and etiological profile of hypercalcemia in hospitalized Asian-Indian patients and its association with 6-month mortality. Materials and Methods: We conducted a prospective observational study wherein all the patients (aged >12 years) admitted to the general medicine wards of a tertiary care hospital in North India between January 1, 2016, and June 30, 2017, were screened. Finally, patients with sustained hypercalcemia (defined as corrected serum total calcium ≥10.4 mg/dl documented twice at least 24 h apart) were included in this study. These patients were followed up throughout the hospital course and thereafter till 6 months from the date of discharge. Results: Out of 9902 patients, 150 patients had sustained hypercalcemia (prevalence 1.5%). The most common cause of hypercalcemia was malignancy (41.3%), followed by primary hyperparathyroidism (PHPT, 32.7%). Vitamin D intoxication was responsible for hypercalcemia in 8.7% of patients; 2.7% of patients had hypercalcemia of advanced chronic liver disease. Nevertheless, a definite etiology could not be identified in 7.3% of the patients with hypercalcemia. At the end of 6 months of follow-up, the cumulative mortality rate was 28%. Underlying malignancy and higher calcium levels were the significant determinants of mortality. Conclusions: The prevalence of hypercalcemia in Asian-Indian patients admitted to a tertiary care hospital was 1.5%. The most common etiology was malignancy, followed by PHPT.

Diagnostic Accuracy of FIB-4 and FIB-5 Scores as Compared to Fibroscan for Assessment of Liver Fibrosis in Patients With Non-Alcoholic Fatty Liver Disease.

Introduction Limited access/exorbitant cost of fibroscan and the associated risks with biopsy to assess fibrosis in non-alcoholic fatty liver disease (NAFLD) patients has made exigent demand of serum-based fibrosis scores to be validated for their accuracy and efficacy. The objective of the study was to compare the accuracy of FIB-4 (fibrosis-4) and FIB-5 (fibrofast) scores to rule out advanced fibrosis in NAFLD patients. Methods A total of 145 patients were categorized as group I with mild/moderate fibrosis (MF) comprising of F0 to F2 and group II with advanced fibrosis (AF) comprising of F3 and F4 based on fibroscan kPa (kilopascal) score. Results Group II had significantly higher alanine transaminase (ALT), aspartate transaminase (AST), haemoglobin % (Hb %), bilirubin and alkaline phosphatase (ALP) values and significantly lower platelet count and albumin as compared to group I. The FIB-4 score was significantly higher in group II [1.8 (1.1 - 4.7)], as compared with group I [0.98 (0.63 - 1.67)], p-value = 0.0001. FIB-5 score of group II [-6.4 (-8.8 - 3.4)] was significantly lower as compared with group I [-4.8 (-6.8 - 2.0)], p-value = 0.003. FIB-4 and FIB-5 had area under receiver operator characteristic (AUROC) curve of 0.712 and 0.655, respectively. FIB-4 at cut-off of <2.02 had a negative predictive value (NPV) of 90.7%. FIB-5 at a cut-off of <-7.11 has an NPV of 94.1% and at a cut-off of <-3.24 had an NPV of 88.9%. Conclusion We concluded that both FIB-4 and FIB-5 can be used to rule out advanced fibrosis in NAFLD patients in a resource-limited and indigent setting as both the scores have NPV greater than 90%.

Non-invasive saliva-based screening of high-risk Human Papilloma Virus 16 and 18 in healthy young adults and creating awareness about its vaccination.

CONTEXT: Human Papilloma Virus (HPV) has not only been linked with cervical cancer but also a key player in other types including oral cancer. Vaccine against HPV has shown promising outcomes in protection against cervical cancer. It is suggested that the same vaccine may be a safeguard against oral cancer as well. Since prevalence of oral cancer is on rise because of various reasons besides high-risk sexual behavior, its prevention becomes equally important. AIM: Study aimed at screening saliva samples of healthy young adults to detect the presence of HPV with an intention to increase awareness regarding HPV and its vaccination. SETTINGS AND DESIGN: The study was executed in the department of Biochemistry, AIIMS, Patna. This cross-sectional study included 100 consented healthy undergraduate medical and nursing students. METHODS AND MATERIAL: We isolated DNA from all saliva samples, amplified using multiplex PCR and gel electrophoresed to screen HPV 16 and 18. Feedback about the study in creating awareness regarding HPV and its vaccine was conducted using three-point Likert scale. STATISTICAL ANALYSIS: The collected responses were entered in Microsoft excel. The results were expressed in frequency and percentages. RESULTS: All saliva samples screened were found negative for HPV 16 and 18 DNA. Responses from feedback showed improved knowledge and awareness about the HPV and its vaccine among the participants. CONCLUSION: Even all the saliva samples tested were found negative for HPV DNA, the screening of high-risk HPV in saliva of young medical and nursing students generated curiosity among them to know more about HPV and its vaccine. This exercise may have helped in increasing the acceptance of HPV vaccine and the awareness of getting it at their ideal age to be benefited with dual protection, from oral and cervical (in case of females) cancers lifelong.