Efficacy, Safety and Immunogenicity of Sun's Ranibizumab Biosimilar in Neovascular Age-Related Macular Degeneration: A Phase 3, Double-Blind Comparative Study.

INTRODUCTION: The study aimed to evaluate comparability in terms of efficacy, safety and immunogenicity of Sun's ranibizumab biosimilar with reference ranibizumab in patients with neovascular age-related macular degeneration (nAMD). METHODS: This prospective, randomised, double-blind, two-group, parallel-arm, multicentre, phase 3 comparative study included patients with nAMD ≥ 50 years, randomised (in a 2:1 ratio) in a double-blind manner to receive 0.5 mg (0.05 mL) intravitreal injection of either Sun's ranibizumab or reference ranibizumab in the study eye every 4 weeks until week 16 (total of four doses). RESULTS: Primary endpoint results demonstrated equivalence in the proportion of patients who lost fewer than 15 letters from baseline best-corrected visual acuity (BCVA) to the end of week 16 (99% of patients in Sun's ranibizumab and 100% in reference ranibizumab; p > 0.9999), with the proportional difference (90% confidence interval) at -1% (-2.51, +0.61) lying within a pre-specified equivalence margin. Visual acuity improved by 15 or more letters in 43% of Sun's ranibizumab group and 37% of the reference ranibizumab group (p = 0.4267). The mean increase in BCVA was 15.7 letters in Sun's ranibizumab group and 14.6 letters in the reference ranibizumab group (p < 0.001 within both groups and p = 0.5275 between groups). The mean change in central macular thickness was comparable between groups (p = 0.7946). Anti-ranibizumab antibodies were found in one patient of the reference ranibizumab group, while neutralising antibodies were not found in any patients. Both products were well tolerated. CONCLUSION: Sun's ranibizumab biosimilar is found to be therapeutically equivalent to reference ranibizumab in patients with nAMD. There were no additional safety or immunogenicity concerns. TRIAL REGISTRATION: CTRI/2020/09/027629, registered on 07 September 2020.

Post-settlement dynamics of Japanese flounder Paralichthys olivaceus in Tango Bay: Seasonal patterns in growth, mortality, and recruitment potential.

Japanese flounder Paralichthys olivaceus is one of the most valuable coastal flatfish species in East Asia. To investigate post-settlement growth and mortality, juveniles were sampled in Tango Bay (Japan) weekly throughout the settlement period in 2007 and 2008. Otolith (lapillus) microstructure analysis enabled the categorization of juveniles into six biweekly cohorts each year. Later cohorts exhibited higher growth rates possibly because of higher water temperatures. A key observation was the direct relationship between high mortality and high density in mid-season cohorts in both years, pointing to density-dependent mortality. This increased mortality may be attributed to predation, including cannibalism by earlier cohorts. Furthermore, growth-selective mortality was evident soon after settlement, underscoring the vulnerability of slow growers to predation during the early juvenile stage. Although earlier and later cohorts were less abundant but showed promising recruitment potential, the prospective contribution of mid-season cohorts to the adult population remained uncertain. The results clearly highlight the importance of density-dependent mortality in population regulation in post-settlement Japanese flounder.

Human albumin infusion is safe and effective even in patients without acute kidney injury and spontaneous bacterial peritonitis.

BACKGROUND AND OBJECTIVES: Human albumin (HA) solution is currently recommended only for patients with spontaneous bacterial peritonitis (SBP) and acute kidney injury (AKI). However, its use in hospitalized patients is quite frequent. The objective was to compare the outcomes of patients receiving HA in recommended (Gr. A) vs. non-recommended (Gr. B) indications. METHODS: In this prospective study, consecutive hospitalized patients who received HA were included. Apart from comparing the proportion of patients achieving resolution of hyponatremia, infection and hepatic encephalopathy among Gr. A and Gr. B, we also compared the in-hospital survival and performed a sub-group analysis of patients with the European Association for the Study of the Liver (EASL) acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC). RESULTS: Of the 396 hospitalized patients who received HA, 180 had AKI and/or SBP (Gr. A), and 216 received albumin for non-recommended indications (Gr. B). The mean age, sex and etiology distribution were similar. The total dose of HA was higher (88 ± 61.62 g vs. 71.31 ± 488.17 g; p = 0.003) and the duration longer (4 ± 2.37 vs. 3.4 ± 1.82 days; p = 0.005) in Gr. A than B. The resolution of infection and HE was similar among both groups, while hyponatremia resolution was significantly higher in Gr. B (94.7%) than Gr. A (75.6%; p < 0.001). On Kaplan-Meier analysis, survival was significantly higher in Gr. B (94%) than Gr. A (78.9%; p < 0.001). The incidence of albumin-induced fluid overload was comparable (2.8% vs. 1.4%; p = 0.32). Patients with ACLF were sicker with a higher incidence of microbiologically proven infection, hepatic encephalopathy (HE) and hyponatremia than in the DC group. Resolution of infection and hyponatremia and in-hospital survival was significantly lower in the ACLF group (72.5%) than in the DC group (92.7%; p < 0.001). Eighty-six per cent of patients achieved resolution of ACLF. CONCLUSIONS: HA infusion is safe and effective even in patients without AKI and SBP and leads to the resolution of infection, hyponatremia, HE and ACLF.

Comparison of western diet-induced obesity and streptozotocin mouse models: insights into energy balance, somatosensory dysfunction, and cardiac autonomic neuropathy.

Metabolic disorders such as obesity and type 2 diabetes (T2D) are increasingly prevalent worldwide, necessitating a deeper comprehension of their underlying mechanisms. However, translating findings from animal research to human patients remains challenging. This study aimed to investigate the long-term effects of Streptozotocin (STZ) on metabolic, cardiac, and somatosensory function in mice fed a Western diet (WD) of high fat, sucrose, and cholesterol with low doses of STZ administration compared to mice fed WD alone. In our research, we thoroughly characterized energy balance and glucose homeostasis, as well as allodynia and cardiac function, all of which have been previously shown to be altered by WD feeding. Notably, our findings revealed that the treatment of WD-fed mice with STZ exacerbated dysfunction in glucose homeostasis via reduced insulin secretion in addition to impaired peripheral insulin signaling. Furthermore, both WD and WD + STZ mice exhibited the same degree of cardiac autonomic neuropathy, such as reduced heart rate variability and decreased protein levels of cardiac autonomic markers. Furthermore, both groups developed the same symptoms of neuropathic pain, accompanied by elevated levels of activating transcription factor 3 (Atf3) in the dorsal root ganglia. These discoveries enhance our understanding of metabolic activity, insulin resistance, neuropathy, and cardiac dysfunction of diet-induced models of obesity and diabetes. The exacerbation of impaired insulin signaling pathways by STZ did not lead to or worsen cardiac and somatosensory dysfunction. Additionally, they offer valuable insights into suitable diet induced translational mouse models, thereby advancing the development of potential interventions for associated conditions.

Hypergraph factorization for multi-tissue gene expression imputation.

Integrating gene expression across tissues and cell types is crucial for understanding the coordinated biological mechanisms that drive disease and characterise homeostasis. However, traditional multitissue integration methods cannot handle uncollected tissues or rely on genotype information, which is often unavailable and subject to privacy concerns. Here we present HYFA (Hypergraph Factorisation), a parameter-efficient graph representation learning approach for joint imputation of multi-tissue and cell-type gene expression. HYFA is genotype-agnostic, supports a variable number of collected tissues per individual, and imposes strong inductive biases to leverage the shared regulatory architecture of tissues and genes. In performance comparison on Genotype-Tissue Expression project data, HYFA achieves superior performance over existing methods, especially when multiple reference tissues are available. The HYFA-imputed dataset can be used to identify replicable regulatory genetic variations (eQTLs), with substantial gains over the original incomplete dataset. HYFA can accelerate the effective and scalable integration of tissue and cell-type transcriptome biorepositories.

Evanescent wave in multiple slit diffraction and n-array antennas in metamaterial using Cesàro convergence.

In this paper, we study Multiple slit diffraction and n- array linear antennae in negative refractive index material. We show that the evanescent wave plays a vital role in the near-field term. The evanescent wave grows significantly, unlike in conventional materials, and satisfies a novel kind of convergence known as Cesàro convergence. We calculate the intensity of multiple slits and the antenna's amplification factor (AF) in terms of the Riemann zeta function. We further demonstrate that the Riemann zeta function gives rise to additional nulls. We deduce that all the diffraction scenarios in which the traveling wave satisfies the geometric series in the medium of the positive refractive index will enhance the evanescent wave, which satisfies Cesàro convergence in the medium of the negative refractive index.

Fecal microbiome transplantation and tributyrin improves early cardiac dysfunction and modifies the BCAA metabolic pathway in a diet induced pre-HFpEF mouse model.

More than 50% of patients with heart failure present with heart failure with preserved ejection fraction (HFpEF), and 80% of them are overweight or obese. In this study we developed an obesity associated pre-HFpEF mouse model and showed an improvement in both systolic and diastolic early dysfunction following fecal microbiome transplant (FMT). Our study suggests that the gut microbiome-derived short-chain fatty acid butyrate plays a significant role in this improvement. Cardiac RNAseq analysis showed butyrate to significantly upregulate ppm1k gene that encodes protein phosphatase 2Cm (PP2Cm) which dephosphorylates and activates branched-chain α-keto acid dehydrogenase (BCKDH) enzyme, and in turn increases the catabolism of branched chain amino acids (BCAAs). Following both FMT and butyrate treatment, the level of inactive p-BCKDH in the heart was reduced. These findings show that gut microbiome modulation can alleviate early cardiac mechanics dysfunction seen in the development of obesity associated HFpEF.

On Representation Knowledge Distillation for Graph Neural Networks.

Knowledge distillation (KD) is a learning paradigm for boosting resource-efficient graph neural networks (GNNs) using more expressive yet cumbersome teacher models. Past work on distillation for GNNs proposed the local structure preserving (LSP) loss, which matches local structural relationships defined over edges across the student and teacher's node embeddings. This article studies whether preserving the global topology of how the teacher embeds graph data can be a more effective distillation objective for GNNs, as real-world graphs often contain latent interactions and noisy edges. We propose graph contrastive representation distillation (G-CRD), which uses contrastive learning to implicitly preserve global topology by aligning the student node embeddings to those of the teacher in a shared representation space. Additionally, we introduce an expanded set of benchmarks on large-scale real-world datasets where the performance gap between teacher and student GNNs is non-negligible. Experiments across four datasets and 14 heterogeneous GNN architectures show that G-CRD consistently boosts the performance and robustness of lightweight GNNs, outperforming LSP (and a global structure preserving (GSP) variant of LSP) as well as baselines from 2-D computer vision. An analysis of the representational similarity among teacher and student embedding spaces reveals that G-CRD balances preserving local and global relationships, while structure preserving approaches are best at preserving one or the other.

Homologous pairing in short double-stranded DNA-grafted colloidal microspheres.

Homologous pairing (HP), i.e., the pairing of similar or identical double-stranded DNA, is an insufficiently understood fundamental biological process. HP is now understood to also occur without protein mediation, but crucial mechanistic details remain poorly established. Unfortunately, systematic studies of sequence dependence are not practical due to the enormous number of nucleotide permutations and multiple possible conformations involved in existing biophysical strategies even when using as few as 150 basepairs. Here, we show that HP can occur in DNA as short as 18 basepairs in a colloidal microparticle-based system. Exemplary systematic studies include resolving opposing reports of the impact of % AT composition, validating the impact of nucleotide order and triplet framework and revealing isotropic bendability to be crucial for HP. These studies are enabled by statistical analysis of crystal size and fraction within coexisting fluid-crystal phases of double-stranded DNA-grafted colloidal microspheres, where crystallization is predicated by HP.

A Study of Variations of the Stomach in Adults and Growth of the Fetal Stomach.

The stomach is a site for various pathological conditions like congestive hypertrophic pyloric stenosis, peptic ulcer, gastroesophageal reflux disease (GERD), and carcinoma of the stomach. Further, for the treatment of obesity too, surgical manipulation of the stomach is done by a bariatric surgeon. With the availability of a wide range of diagnostic tools like barium meals, USG, CT scan, MRI, and endoscopy, it is possible to identify the variations in the position and shape of the stomach and developmental defects while diagnosing diseases. As thorough knowledge of stomach position and variations will help in preoperative planning and preventing inadvertent damage during surgeries, this topic was taken up for research. Aims and objectives This study aims to study the variations of the stomach in human cadavers and dead fetuses with regard to its length, shape, capacity, ends, curvatures, and mucosal folding and classify them into various groups. In addition, this study also aims to assess the pattern of growth of the stomach in fetuses. Material and methods The stomachs of 50 adult cadavers and 20 dead fetuses were studied by standard dissection method, concerning their topography, shape, level of the cardiac and pyloric orifice, cardiac angle, length of greater (GC) and lesser curvatures (LC), pyloric sphincter, volume, and mucosal folds. Results The stomach was located in the left hypochondriac quadrant in 78% of the samples and in relation to the 7th costal cartilage in 64%. The two main types of classification established were Type I (variation in position along the vertical axis) in 4% and Type II (variation in position along the transverse axis) in 14%. Type III classification comprised the variations in shape, with a J-shaped stomach in 58%, cylindrical in 20%, crescentic in 14%, and reversed L in 8%. The average length showed significant differences in males, 19±2.48 cm vis-a-vis females, 17.1±2.01 cm. In 66% of the cases, the cardiac orifice was to the left of the midline behind the 7th costal cartilage, and the pyloric orifice was to the right, 1.2 cm to the midline and in the transpyloric plane in 76%. The average GC and LC were 33.6±1.43 cm and 27±5.28 cm, respectively. GC was more significant in males. The average length and diameter of the pyloric canal were about 3.56±0.38 cm & 0.77±0.23 cm, respectively. The thickness of the pyloric sphincter did not show a significant gender difference. The average volume was 289.88±69.15 ml. Rugae were normally spaced in 68%, nearly spaced in 18%, and widely spaced in 6%. The fetal stomach measurements were significantly correlated to gestational age and showed linear growth. Conclusion The study of the morphology of the stomach and its variations are important not only to surgeons and anatomists but also to gastroenterologists. The linear growth of the stomach in embryos helps radiologists and obstetricians to diagnose intrauterine growth retardation (IUGR) and congenital anomalies early.

A perspective of yoga on smartphone addiction: A narrative review.

Evolution in technology is drastically becoming automatic and making life easier. Among those technologies, smartphones are fast-changing technology that is equipping humans to work from anywhere. Frequent usage and dependency on smartphones have increased, which in turn contributes to changes in psychosocial behavioral aspects. Addiction plays an important role in modifying the healthy habits of individuals. Problematic usage of smartphones affects both physical and psychosocial health and emerges as a cornerstone of psychosocial disorder. However, there is a dearth of data to understand the core concepts of smartphone addiction and there is a need to understand from the broader perspective. Yoga is considered one of the viable protocols to provide the way for digital detoxification from technology and smartphone addiction by promoting self-regulation. Yoga brings back a healthy living style, which allows individuals to have enough physical activity through asanas, emotional stability, and awareness through meditation and breathing practices. We hypothesize that a holistic approach to yoga can regulate the symptoms associated with smartphone addiction by increasing the stability of the body and mind and promoting emotional detachment and self-regulation, which play an important role in the de-addiction process.

Evaluation of Immediately Loaded Parallel Conical Connection Implants with Platform Switch in the Maxillary Esthetic Zone: A Prospective Clinical Study.

AIM: To assess immediately loaded parallel conical connection (Nobel Biocare) implants with platform switch design in the maxillary esthetic zone for soft and hard tissue changes. MATERIALS AND METHODS: A total of 20 patients (n = 20) underwent prosthetic replacement of the missing maxillary anterior tooth, with an immediately loaded parallel conical connection implant (Noble Biocare, Sweden) having a platform switch design. The size of the implant was 3.75 mm in width and 13 mm in length for all patients and placement followed a standardized surgical protocol. Postoperatively, acrylic provisionalization was done within 48 hours followed by a definitive zirconia prosthesis in the 3rd month. Clinically and radiographically, the implants were evaluated for hard tissue (bone density, implant stability, crestal bone loss) and soft tissue changes (mucosal thickness-MT, sulcus probing depth-PD, bleeding on probing-BOP, width of keratinized gingiva-KG) at baseline till 36 months with follow-up intervals after loading. RESULTS: All patients showed uneventful healing. The difference in implant stability and density scores was significant (p <0.05*) from baseline to 36 months indicating bone formation and osseointegration of the implant. Bleeding on probing was not observed, and probing depth remained within the acceptable range (≤5 mm) at all time intervals after loading. The marginal bone loss was minimal (≤0.2 mm annually) with the absence of implant mobility and without any peri-implant radiolucency. The thickness of the gingiva (3.47 ± 0.34 mm) and width of keratinized gingiva (2.46 ± 0.39 mm) remained within reasonable limits at the 36th month with acceptable esthetic appearance. CONCLUSION: In the present study, immediate loading of Nobel parallel conical connection implant in the maxillary anterior region provided adequate primary stability, minimal marginal bone loss, and increased bone density indicating earlier osseointegration. Decreased probing depth, absence of bleeding on probing, and adequate tissue collar at the neck showed better soft tissue emergence in the esthetic zone. The platform switch design demonstrated promising results and therefore can be used as an alternative to the conventional method. CLINICAL SIGNIFICANCE: The present study results suggest that parallel conical connection implants (Nobel Biocare) with TiUnite surface, built-in platform switch combined with conical connection interface, parallel walled body, tapered apex, and double threads from tip to platform are all designed to provide high primary stability and support immediate function protocol, hence can be used flexibly in different bone densities.

LXR agonist modifies neuronal lipid homeostasis and decreases PGD2 in the dorsal root ganglia in western diet-fed mice.

The prevalence of peripheral neuropathy is high in diabetic and overweight populations. Chronic neuropathic pain, a symptom of peripheral neuropathy, is a major disabling symptom that leads to a poor quality of life. Glucose management for diabetic and prediabetic individuals often fail to reduce or improve pain symptoms, therefore, exploring other mechanisms is necessary to identify effective treatments. A large body of evidence suggest that lipid signaling may be a viable target for management of peripheral neuropathy in obese individuals. The nuclear transcription factors, Liver X Receptors (LXR), are known regulators of lipid homeostasis, phospholipid remodeling, and inflammation. Notably, the activation of LXR using the synthetic agonist GW3965, delayed western diet (WD)-induced allodynia in rodents. To further understand the neurobiology underlying the effect of LXR, we used translating ribosome affinity purification and evaluated translatomic changes in the sensory neurons of WD-fed mice treated with the LXR agonist GW3965. We also observed that GW3965 decreased prostaglandin levels and decreased free fatty acid content, while increasing lysophosphatidylcholine, phosphatidylcholine, and cholesterol ester species in the sensory neurons of the dorsal root ganglia (DRG). These data suggest novel downstream interplaying mechanisms that modifies DRG neuronal lipid following GW3965 treatment.

LXR agonist improves peripheral neuropathy and modifies PNS immune cells in aged mice.

BACKGROUND: Peripheral neuropathy is a common and progressive disorder in the elderly that interferes with daily activities. It is of importance to find efficient treatments to treat or delay this age-related neurodegeneration. Silencing macrophages by reducing foamy macrophages showed significant improvement of age-related degenerative changes in peripheral nerves of aged mice. We previously demonstrated that activation of the cholesterol sensor Liver X receptor (LXR) with the potent agonist, GW3965, alleviates pain in a diet-induced obesity model. We sought to test whether LXR activation may improve neuropathy in aged mice. METHODS: 21-month-old mice were treated with GW3965 (25 mg/Kg body weight) for 3 months while testing for mechanical allodynia and thermal hyperalgesia. At termination, flow cytometry was used to profile dorsal root ganglia and sciatic nerve cells. Immune cells were sorted and analyzed for cholesterol and gene expression. Nerve fibers of the skin from the paws were analyzed. Some human sural nerves were also evaluated. Comparisons were made using either t test or one-way ANOVA. RESULTS: Treatment with GW3965 prevented the development of mechanical hypersensitivity and thermal hyperalgesia over time in aged mice. We also observed change in polarization and cholesterol content of sciatic nerve macrophages accompanied by a significant increase in nerve fibers of the skin. CONCLUSIONS: These results suggest that activation of the LXR may delay the PNS aging by modifying nerve-immune cell lipid content. Our study provides new potential targets to treat or delay neuropathy during aging.

Multigraph Transformer for Free-Hand Sketch Recognition.

Learning meaningful representations of free-hand sketches remains a challenging task given the signal sparsity and the high-level abstraction of sketches. Existing techniques have focused on exploiting either the static nature of sketches with convolutional neural networks (CNNs) or the temporal sequential property with recurrent neural networks (RNNs). In this work, we propose a new representation of sketches as multiple sparsely connected graphs. We design a novel graph neural network (GNN), the multigraph transformer (MGT), for learning representations of sketches from multiple graphs, which simultaneously capture global and local geometric stroke structures as well as temporal information. We report extensive numerical experiments on a sketch recognition task to demonstrate the performance of the proposed approach. Particularly, MGT applied on 414k sketches from Google QuickDraw: 1) achieves a small recognition gap to the CNN-based performance upper bound (72.80% versus 74.22%) and infers faster than the CNN competitors and 2) outperforms all RNN-based models by a significant margin. To the best of our knowledge, this is the first work proposing to represent sketches as graphs and apply GNNs for sketch recognition. Code and trained models are available at https://github.com/PengBoXiangShang/multigraph_transformer.

Loss of C2 Domain Protein (C2CD5) Alters Hypothalamic Mitochondrial Trafficking, Structure, and Function.

INTRODUCTION: Mitochondria are essential organelles required for several cellular processes ranging from ATP production to cell maintenance. To provide energy, mitochondria are transported to specific cellular areas in need. Mitochondria also need to be recycled. These mechanisms rely heavily on trafficking events. While mechanisms are still unclear, hypothalamic mitochondria are linked to obesity. METHODS: We used C2 domain protein 5 (C2CD5, also called C2 domain-containing phosphoprotein [CDP138]) whole-body KO mice primary neuronal cultures and cell lines to perform electron microscopy, live cellular imaging, and oxygen consumption assay to better characterize mitochondrial alteration linked to C2CD5. RESULTS: This study identified that C2CD5 is necessary for proper mitochondrial trafficking, structure, and function in the hypothalamic neurons. We previously reported that mice lacking C2CD5 were obese and displayed reduced functional G-coupled receptor, melanocortin receptor 4 (MC4R) at the surface of hypothalamic neurons. Our data suggest that in neurons, normal MC4R endocytosis/trafficking necessities functional mitochondria. DISCUSSION: Our data show that C2CD5 is a new protein necessary for normal mitochondrial function in the hypothalamus. Its loss alters mitochondrial ultrastructure, localization, and activity within the hypothalamic neurons. C2CD5 may represent a new protein linking hypothalamic dysfunction, mitochondria, and obesity.

Vagal neuron expression of the microbiota-derived metabolite receptor, free fatty acid receptor (FFAR3), is necessary for normal feeding behavior.

OBJECTIVE: The vagus nerve provides a direct line of communication between the gut and the brain for proper regulation of energy balance and glucose homeostasis. Short-chain fatty acids (SCFAs) produced via gut microbiota fermentation of dietary fiber have been proposed to regulate host metabolism and feeding behavior via the vagus nerve, but the molecular mechanisms have not yet been elucidated. We sought to identify the G-protein-coupled receptors within vagal neurons that mediate the physiological and therapeutic benefits of SCFAs. METHODS: SCFA, particularly propionate, signaling occurs via free fatty acid receptor 3 (FFAR3), that we found expressed in vagal sensory neurons innervating throughout the gut. The lack of cell-specific animal models has impeded our understanding of gut/brain communication; therefore, we generated a mouse model for cre-recombinase-driven deletion of Ffar3. We comprehensively characterized the feeding behavior of control and vagal-FFAR3 knockout (KO) mice in response to various conditions including fasting/refeeding, western diet (WD) feeding, and propionate supplementation. We also utilized ex vivo organotypic vagal cultures to investigate the signaling pathways downstream of propionate FFAR3 activation. RESULTS: Vagal-FFAR3KO led to increased meal size in males and females, and increased food intake during fasting/refeeding and WD challenges. In addition, the anorectic effect of propionate supplementation was lost in vagal-FFAR3KO mice. Sequencing approaches combining ex vivo and in vivo experiments revealed that the cross-talk of FFAR3 signaling with cholecystokinin (CCK) and leptin receptor pathways leads to alterations in food intake. CONCLUSION: Altogether, our data demonstrate that FFAR3 expressed in vagal neurons regulates feeding behavior and mediates propionate-induced decrease in food intake.

Immature Platelet Fraction: Its Clinical Utility in Thrombocytopenia Patients.

Objectives Etiology of thrombocytopenia is multifactorial and its pathogenesis should be distinguished for appropriate management. Newly formed immature platelets are called reticulated platelets (RPs) and can be estimated in peripheral blood using automated hematology analyzers, which express them as immature platelet fraction (IPF). In the present study we intend to assess and establish the clinical utility of IPF in differentiating the two major causes of thrombocytopenia-decreased production and increased destruction of platelets-along with determining its significance in monitoring patients with thrombocytopenia. Materials and Methods Sixty-one cases of thrombocytopenia and 101 healthy controls with normal platelet count were included in the study. IPF and all the other usual blood cell parameters were measured using a fully automated hematology analyzer. Based on the pathogenesis of thrombocytopenia, the cases were divided into groups and the difference in IPF value between the groups was evaluated. Results The reference range of IPF among healthy controls was estimated to be 0.7 to 5.7%. The mean IPF was significantly higher in patients with increased peripheral destruction of platelets (13.4%) as compared to patients with decreased production of platelets (4.6%). The optimal cutoff value of IPF for differentiating patients with increased peripheral destruction of platelets from patients with decreased production of platelets was 5.95% with a sensitivity of 88% and specificity of 75.9%. Conclusion Measurement of IPF is useful for detecting evidence of increased platelet production and helps in the initial evaluation of thrombocytopenia patients. It is a novel diagnostic method which can be used to differentiate patients with thrombocytopenia due to increased destruction of platelets from patients with thrombocytopenia due to bone marrow failure/suppression.

An Adrenocortical Carcinoma Evolving After Nine Years of Latency From a Small Adrenal Incidentaloma.

Adrenal incidentalomas (AIs) are common incidental findings in medical practice with clinical significance. Although most AIs are nonsecretory and nonmalignant, they require a short course of follow-up over one to two years to rule out malignancy or hormonal secretion according to clinical practice guidelines. However, this can result in some adrenocortical carcinomas (ACCs) being missed if they transform at a later stage or evolve slowly. Here, we report one such case of an AI, which although remained indolent, eventually transformed into an ACC many years after the initial detection.

Toll-like Receptor-4 (TLR4) Agonist-Based Intranasal Nanovaccine Delivery System for Inducing Systemic and Mucosal Immunity.

Eliciting a robust immune response at mucosal sites is critical in preventing the entry of mucosal pathogens such as influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This task is challenging to achieve without the inclusion of a strong and safe mucosal adjuvant. Previously, inulin acetate (InAc), a plant-based polymer, is shown to activate toll-like receptor-4 (TLR4) and elicit a robust systemic immune response as a vaccine adjuvant. This study investigates the potential of nanoparticles prepared with InAc (InAc-NPs) as an intranasal vaccine delivery system to generate both mucosal and systemic immune responses. InAc-NPs (∼250 nm in diameter) activated wild-type (WT) macrophages but failed to activate macrophages from TLR4 knockout mice or WT macrophages when pretreated with a TLR4 antagonist (lipopolysaccharide-RS (LPS-RS)), which indicates the selective nature of a InAc-based nanodelivery system as a TLR4 agonist. Intranasal immunization using antigen-loaded InAc-NPs generated ∼65-fold and 19-fold higher serum IgG1 and IgG2a titers against the antigen, respectively, as compared to PLGA-NPs as a delivery system. InAc-NPs have also stimulated the secretion of sIgA at various mucosal sites, including nasal-associated lymphoid tissues (NALTs), lungs, and intestine, and produced a strong memory response indicative of both humoral and cellular immune activation. Overall, by stimulating both systemic and mucosal immunity, InAc-NPs laid a basis for a potential intranasal delivery system for mucosal vaccination.