Discovery of a novel and highly selective JAK3 inhibitor as a potent hair growth promoter.

JAK-STAT signalling pathway inhibitors have emerged as promising therapeutic agents for the treatment of hair loss. Among different JAK isoforms, JAK3 has become an ideal target for drug discovery because it only regulates a narrow spectrum of γc cytokines. Here, we report the discovery of MJ04, a novel and highly selective 3-pyrimidinylazaindole based JAK3 inhibitor, as a potential hair growth promoter with an IC50 of 2.03 nM. During in vivo efficacy assays, topical application of MJ04 on DHT-challenged AGA and athymic nude mice resulted in early onset of hair regrowth. Furthermore, MJ04 significantly promoted the growth of human hair follicles under ex-vivo conditions. MJ04 exhibited a reasonably good pharmacokinetic profile and demonstrated a favourable safety profile under in vivo and in vitro conditions. Taken together, we report MJ04 as a highly potent and selective JAK3 inhibitor that exhibits overall properties suitable for topical drug development and advancement to human clinical trials.

An Insight Into Various Manifestations of Leptospirosis: A Unique Case Series From a State in Eastern India.

BACKGROUND: Leptospirosis presents with highly variable clinical manifestations affecting different organ systems in different individuals. The presentation ranges from an asymptomatic or mild disease to a severe disease associated with multiorgan failure and higher mortality. Leptospirosis is highly underreported due to a lack of diagnostic modalities and less suspicion among clinicians. METHODOLOGY: We present this single-center retrospective case series of 12 cases, which include various common and uncommon scenarios by which the disease can present and can be missed due to lack of suspicion. The study contains individual patient characteristics including demographic, laboratory, clinical, and treatment data. The association between these variables and mortality was analyzed using p-values and results were described. A p-value of<0.05 was considered statistically significant. RESULTS: A total of 12 cases were included in the study. The male-to-female ratio was 3:1. The mean age was higher (37.75±9.81 years) in cases who died than those who recovered (34.25±14.09). Factors like history of alcoholism, presence of chronic liver disease (CLD), jaundice, acute renal failure, requirement of dialysis, and requirement of intensive care were significantly associated with increased risk of death (odds ratio >1, p-value <0.05). The most common symptom of presentation was fever in 11 (91.66%) cases. Jaundice and renal failure were significantly associated with death (odds ratio 1.2, p-value 0.04). The requirement of intensive care treatment (odds ratio 2.1, p-value 0.05) and dialysis (odds ratio 39.66, p-value 0.03) were also significantly associated with death. The percentage of death was lower in the group of patients who received combination antibiotic therapy. CONCLUSION: Leptospirosis has varied presentations in different individuals and the diagnosis can be missed due to lack of specific signs and symptoms. Severe diseases involving multiple organs and preexisting comorbidities are associated with higher mortality rates. Timely diagnosis and treatment are necessary to reduce mortality and increase survival.

Combining Bioorthogonal Chemistry with Fluorescent Silica Nanoparticles for the Ultrasensitive Detection of the HIV-1 p24 Antigen.

Early detection and viral concentration monitoring of human immunodeficiency virus in resource-poor settings are important to control disease spread and reduce mortality. Nucleic acid amplification tests are expensive for low-resource settings. Lateral flow antibody tests are not sensitive if testing is performed within 7-10 days, and these tests are not quantitative. We describe a signal enhancement technique based on fluorescent silica nanoparticles and bioorthogonal chemistries for the femtomolar detection of the HIV-1 p24 antigen. We developed a magnetic bead-based assay, wherein we used fluorescent-dye-encapsulated silica nanoparticles as reporters. The number of reporters was increased by using bioorthogonal chemistry to provide signal enhancement. The limit and range of detection of the sandwich immunoassay using alternating multiple layers for p24 in human serum were found to be 46 fg/mL (1.84 fM) and 46 fg/mL to 10 ng/mL, respectively. This simple assay was 217-fold higher in sensitivity compared to that of commercial enzyme-linked immunoassays (limit of detection of 10 pg/mL).

Exploring the role of in-patient magnetic resonance imaging use among admitted ischemic stroke patients in improving patient outcomes and reducing healthcare resource utilization.

Purpose: Despite the diagnostic and etiological significance of in-patient MRI in ischemic stroke (IS), its utilization is considered resource-intensive, expensive, and thus limiting feasibility and relevance. This study investigated the utilization of in-patient MRI for IS patients and its impact on patient and healthcare resource utilization outcomes. Methods: This retrospective registry-based study analyzed 1,956 IS patients admitted to Halifax's QEII Health Centre between 2015 and 2019. Firstly, temporal trends of MRI and other neuroimaging utilization were evaluated. Secondly, we categorized the cohort into two groups (MRI vs. No MRI; in addition to a non-contrast CT) and investigated adjusted differences in patient outcomes at admission, discharge, and post-discharge using logistic regression. Additionally, we analyzed healthcare resource utilization using Poisson log-linear regression. Furthermore, patient outcomes significantly associated with MRI use underwent subgroup analysis for stroke severity (mild stroke including transient ischemic attack vs. moderate and severe stroke) and any acute stage treatment (thrombolytic or thrombectomy or both vs. no treatment) subgroups, while using an age and sex-adjusted logistic regression model. Results: MRI was used in 40.5% patients; non-contrast CT in 99.3%, CT angiogram in 61.8%, and CT perfusion in 50.3%. Higher MRI utilization was associated with male sex, younger age, mild stroke, wake-up stroke, and no thrombolytic or thrombectomy treatment. MRI use was independently associated with lower in-hospital mortality (adjusted OR, 0.23; 95% CI, 0.15-0.36), lower symptomatic neurological status changes (0.64; 0.43-0.94), higher home discharge (1.32; 1.07-1.63), good functional outcomes at discharge (mRS score 0-2) (1.38; 1.11-1.72), lower 30-day stroke re-admission rates (0.48; 0.26-0.89), shorter hospital stays (regression coefficient, 0.92; 95% CI, 0.90-0.94), and reduced direct costs of hospitalization (0.90; 0.89-0.91). Subgroup analysis revealed significantly positive association of MRI use with most patient outcomes in moderate and severe strokes subgroup and non-acutely treated subgroup. Conversely, outcomes in mild strokes (including TIAs) subgroup and acute treatment subgroup were comparable regardless of MRI use. Conclusion: A substantial proportion of admitted IS patients underwent MRI, and MRI use was associated with improved patient outcomes and reduced healthcare resource utilization. Considering the multifactorial nature of IS patient outcomes, further randomized controlled trials are suggested to investigate the role of increased MRI utilization in optimizing in-patient IS management.

Polymers and their engineered analogues for ocular drug delivery: Enhancing therapeutic precision.

Ocular drug delivery is constrained by anatomical and physiological barriers, necessitating innovative solutions for effective therapy. Natural polymers like hyaluronic acid, chitosan, and gelatin, alongside synthetic counterparts such as PLGA and PEG, have gained prominence for their biocompatibility and controlled release profiles. Recent strides in polymer conjugation strategies have enabled targeted delivery through ligand integration, facilitating tissue specificity and cellular uptake. This versatility accommodates combined drug delivery, addressing diverse anterior (e.g., glaucoma, dry eye) and posterior segment (e.g., macular degeneration, diabetic retinopathy) afflictions. The review encompasses an in-depth exploration of each natural and synthetic polymer, detailing their individual advantages and disadvantages for ocular drug delivery. By transcending ocular barriers and refining therapeutic precision, these innovations promise to reshape the management of anterior and posterior segment eye diseases.

Percentage of patients shifting to another treatment modality: An experience-guided decision.

OBJECTIVE: This study aimed to assess the frequency with which orthodontic patients decided to shift to another type of orthodontic appliance, among conventional metal brackets, ceramic brackets, lingual brackets and clear aligner, based on their personal experiences of pain, ulcers, bad breath, hygiene issues and social difficulties. MATERIAL AND METHODS: This study comprises of patients seeking orthodontic treatment. The sample (n = 500; age group = 19-25 years) was divided equally into four groups based on the treatment modality: conventional metal brackets, ceramic brackets, lingual brackets and clear aligner. Patients rated the questionnaire using a visual analogue scale, to assess variables (such as pain, ulcer etc) that impact various treatment modalities. Subsequently, patients from all groups provided feedback regarding their treatment experiences, and expressed their preference for an alternative modality. Intergroup comparison among the four groups was done using one-way analysis of variance with Tukey's HSD post-hoc test (p ≤ 0.05). RESULTS: Patients who received lingual brackets reported higher levels of pain and ulceration, as compared to those who received clear aligners. All four groups showed statistically significant differences for ulcers during treatment (p ≤ 0.05). Of the 125 patients who received conventional metal brackets, 28% expressed a preference for clear aligner therapy, while 20% preferred ceramic brackets. In the lingual group, 56% of 125 patients preferred clear aligner therapy, and 8% preferred ceramic brackets to complete their treatment. In the ceramic group, 83% did not want to switch, whereas 17% desired to switch to clear aligner, while in aligner group no patient desired to switch. CONCLUSIONS: A higher percentage of patients from lingual brackets group chose to shift to clear aligners, followed by conventional metal brackets group and by ceramic brackets group, in this descending order. The clear aligner group demonstrated fewer issues than the other treatment modalities.

Scrub typhus in pregnancy - A threat to maternal and fetal outcome.

Background and Objectives: Scrub typhus is an acute febrile illness transmitted by the bite of trombiculid mite in the larval stage. Scrub typhus is rare in pregnancy and there is paucity of data on the clinical outcome of scrub typhus during pregnancy. Material and Methods: We present five cases of scrub typhus complicating pregnancy who were admitted in the obstetric ward at AIIMS Rishikesh, India during the antenatal period for management. Results: The first patient presented at term pregnancy in semiconscious state while the rest were preterm between 31 and 34 weeks period of gestation. The age at presentation was 21-31 years. All five had febrile illness of >5 days' duration along with cough. Fever investigations like blood culture, peripheral smear for malarial parasite, dengue serology, widal test, and urine culture were negative. Serology for scrub typhus was positive in all. Once diagnosis was confirmed for scrub typhus, patients were given the drug of choice azithromycin 500 mg twice daily for five days. Scrub typhus complicating pregnancy led to maternal mortality in one patient. It resulted in one preterm delivery, one intrauterine fetal death, and rest three were delivered at term with good perinatal outcome. Conclusion: Scrub typhus is common in endemic areas like Uttarakhand, India. It has a poor fetal outcome. If diagnosed early and treatment started, maternal and fetal prognosis can be favorable. As large case series are unavailable in literature, it is difficult to predict the course of disease which at times may be fulminant.

Internet addiction among MBBS students at a New Delhi medical college: Prevalence and determinants of a silent pandemic.

Background and Objective: The 21st century has witnessed a surge in global internet usage, particularly in developing nations like India. Internet addiction, also known as pathological internet use (PIU) or internet addiction (IA), has emerged as a mental health concern, especially among university students. This study aimed to investigate the prevalence of IA among MBBS students in a medical college in Delhi, India, and explore the association of IA with sociodemographic and internet usage patterns. Materials and Methods: A cross-sectional observational study was conducted among 300 undergraduate medical students. Data was collected using a self-administered questionnaire, which included the Internet Addiction Test (IAT) developed by Dr. Kimberley Young. The IAT measures various aspects of internet use, and scores are categorized as normal user, mild addiction, moderate addiction, and severe addiction. Descriptive statistics and chi-square tests were used for data analysis. Results: The mean age of onset of internet use was 14.4 ± 1.6 years. Smartphones were the most common devices used for internet access (96.3%), and the mean daily internet usage was 2.9 h ± 0.9 (standard deviation [SD]). The study found that 70.7% of students maintained a permanent login status. The majority of subjects used the Internet for coursework (89.7%) and information searches (88.7%). The prevalence of IA was significant, with 90% of participants being addicted to varying degrees. The grading of IA revealed 10% with no addiction, 54.6% with mild addiction, 32% with moderate addiction, and 3.3% with severe addiction. Conclusion: IA is a prevalent public health concern among medical students in Delhi, with a majority of participants being addicted to some extent. Females showed a higher proportion of addiction compared to males. Certain internet activities, such as social networking and watching online videos, were significantly associated with IA. The study highlights the need for recognizing IA as a public health concern and further research to understand its impact on the youth. Longitudinal studies are recommended to observe the development and progression of IA over time.

A novel approach to designing viral precision vaccines applied to SARS-CoV-2.

Efficient precision vaccines against several highly pathogenic zoonotic viruses are currently lacking. Proteolytic activation is instrumental for a number of these viruses to gain host-cell entry and develop infectivity. For SARS-CoV-2, this process is enhanced by the insertion of a furin cleavage site at the junction of the spike protein S1/S2 subunits upstream of the metalloprotease TMPRSS2 common proteolytic site. Here, we describe a new approach based on specific epitopes selection from the region involved in proteolytic activation and infectivity for the engineering of precision candidate vaccinating antigens. This approach was developed through its application to the design of SARS-CoV-2 cross-variant candidates vaccinating antigens. It includes an in silico structural analysis of the viral region involved in infectivity, the identification of conserved immunogenic epitopes and the selection of those eliciting specific immune responses in infected people. The following step consists of engineering vaccinating antigens that carry the selected epitopes and mimic their 3D native structure. Using this approach, we demonstrated through a Covid-19 patient-centered study of a 500 patients' cohort, that the epitopes selected from SARS-CoV-2 protein S1/S2 junction elicited a neutralizing antibody response significantly associated with mild and asymptomatic COVID-19 (p<0.001), which strongly suggests protective immunity. Engineered antigens containing the SARS-CoV-2 selected epitopes and mimicking the native epitopes 3D structure generated neutralizing antibody response in mice. Our data show the potential of this combined computational and experimental approach for designing precision vaccines against viruses whose pathogenicity is contingent upon proteolytic activation.

Evaluation of Dissolution of Pulp by Sodium Hypochlorite when Mixed with Tetrasodic Etidronate and Disodic Ethylenediamine Tetraacetate under Controlled Flow.

Background: Sodium hypochlorite serves as the most efficient root canal irrigating fluid. Objectives: This study's goal was to assess the replenished NaOCl's capacity to dissolve the tissue of pulp when combined with 9% tetrasodic etidronate (Na4HEBP), 18% tetrasodic etidronate (Na4HEBP), and 17% disodic ethylenediaminetetraacetate (Na2EDTA) under continuous controlled administration. Materials and Methods: Hundred and twenty complete undamaged teeth of the anterior mandible extracted due to periodontal problems within forty-eight hours were taken as a source of the pulp tissue. Results: It was found that there was a decrease in the weight of pulp tissue in all groups except negative control. Conclusion: NaOCl's potential to dissolve tissue with chelating agents like EDTA and HEBP inside the root canal was unaffected when there was controlled administration of EDTA and HEBP.

Assessment of Postoperative Swelling and Pain Following Alveolar Ridge Preservation with Different Biomaterials: A Randomized Controlled Trial.

Background: This randomized controlled trial aimed to assess and compare postoperative swelling and pain in patients undergoing alveolar ridge preservation using RidgeMax Pro and AlveoGraft Plus. Methods: A total of 20 patients requiring tooth extraction were enrolled in this study and randomly assigned to two groups: Group A received alveolar ridge preservation with RidgeMax Pro and Group B with AlveoGraft Plus. Postoperative swelling was evaluated by measuring facial dimensions using standardized facial photographs at baseline and at 24, 48, and 72 hours postoperatively. Pain was assessed using a visual analog scale (VAS) at the same time points. Statistical analysis was performed using t-tests and repeated measures ANOVA. Results: Both RidgeMax Pro and AlveoGraft Plus demonstrated effective alveolar ridge preservation without any reported complications. In terms of postoperative swelling, Group A (RidgeMax Pro) exhibited significantly lower facial swelling compared to Group B (AlveoGraft Plus) at all time points (P < 0.05). The mean pain scores on the VAS were consistently lower in Group A than in Group B across the assessment time points (P < 0.05). The trend of reduced swelling and pain in Group A persisted throughout the 72-hour follow-up period. Conclusion: Alveolar ridge preservation with RidgeMax Pro (Trade Name: RidgeMax Pro) resulted in significantly reduced postoperative swelling and pain compared to AlveoGraft Plus (Trade Name: AlveoGraft Plus).

Aesthetic Outcome and Patient Perception of Immediate vs. Delayed Loading of Implant-Supported Single Crowns: A Randomized Controlled Trial.

Background: This randomized controlled trial aimed to compare the aesthetic outcome and patient perception of immediate versus DL of implant-supported single crowns. Methods: A total of 60 patients with a single missing tooth were enrolled and randomly assigned to two groups: immediate loading (IL) and delayed loading (DL). Each group consisted of 30 patients with a total of 30 implants. In the IL group, crowns were loaded onto implants immediately after placement, while in the DL group, a healing period of 3 months was observed before crown placement. Aesthetic outcome was assessed using the Pink Esthetic Score (PES) for soft tissue and the White Esthetic Score (WES) for the crown. Patient perception was evaluated through a visual analog scale (VAS) for satisfaction, comfort, and overall experience. Results: The IL group demonstrated comparable aesthetic outcomes to the DL group, with mean PES and WES scores of 10.2 ± 1.5 and 8.7 ± 1.2, respectively, in the IL group, and 10.5 ± 1.3 and 8.5 ± 1.4 in the DL group. Patient perception in terms of satisfaction, comfort, and overall experience was similarly high in both groups, with VAS scores above 8 for each parameter. Conclusion: This randomized controlled trial suggests that both IL and DL of implant-supported single crowns result in favorable aesthetic outcomes and high levels of patient satisfaction.

Comparison of Different Endodontic Access Cavity Designs on the Fracture Resistance of Tooth in WaveOne Gold and TruNatomy Instrumentation.

Background: An important aspect of the preparation of the access cavity and biomechanical preparation of the root canal is to safeguard as much of the tooth's framework as possible without affecting access and visibility. Objectives: To compare the impact of the conservative design of access preparation and traditional design of access preparation in association with TruNatomy endodontic instrumentation and WaveOne Gold endodontic instrumentation on resistance to fracture by the design of a cavity for endodontic access using finite element analysis. Materials and Methods: Micro-CT radiographic images of 16 human first permanent molars of the mandible were included in the study to create representative finite element analysis computational models. Results: A significant reduction in load for failure after endodontic preparation was observed in TDAP subcategories as compared to specimens with CDAP. However, the reduction in load for failure was comparable in both endodontic instrument systems within the CDAP and TDAP. Conclusion: A significant reduction in load for failure after endodontic preparation was observed in the traditional design of access preparation subcategories as compared to specimens with the conventional design of access preparation.

Nanopatterning Induced Si Doping in Amorphous Ga2O3 for Enhanced Electrical Properties and Ultra-Fast Photodetection.

Ga2O3 has emerged as a promising material for the wide-bandgap industry aiming at devices beyond the limits of conventional silicon. Amorphous Ga2O3 is widely being used for flexible electronics, but suffers from very high resistivity. Conventional methods of doping like ion implantation require high temperatures post-processing, thereby limiting their use. Herein, an unconventional method of doping Ga2O3 films with Si, thereby enhancing its electrical properties, is reported. Ion-beam sputtering (500 eV Ar+) is utilized to nanopattern SiO2-coated Si substrate leaving the topmost part rich in elemental Si. This helps in enhancing the carrier conduction by increasing n-type doping of the subsequently coated 5 nm amorphous Ga2O3 films, corroborated by room-temperature resistivity measurement and valence band spectra, respectively, while the nanopatterns formed help in better light management. Finally, as proof of concept, metal-semiconductor-metal (MSM) photoconductor devices fabricated on doped, rippled films show superior properties with responsivity increasing from 6 to 433 mA W-1 while having fast detection speeds of 861 µs/710 µs (rise/fall time) as opposed to non-rippled devices (377 ms/392 ms). The results demonstrate a facile, cost-effective, and large-area method to dope amorphous Ga2O3 films in a bottom-up approach which may be employed for increasing the electrical conductivity of other amorphous oxide semiconductors as well.

Population Trends of New Prescriptions for Antihyperglycemics and Antihypertensives Between 2014 and 2022.

BACKGROUND: In the wake of pandemic-related health decline and health care disruptions, there are concerns that previous gains for cardiovascular risk factors may have stalled or reversed. Population-level excess burden of drug-treated diabetes and hypertension during the pandemic compared with baseline is not well characterized. We evaluated the change in incident prescription claims for antihyperglycemics and antihypertensives before versus during the pandemic. METHODS AND RESULTS: In this retrospective, serial, cross-sectional, population-based study, we used interrupted time series analyses to examine changes in the age- and sex-standardized monthly rate of incident prescriptions for antihyperglycemics and antihypertensives in patients aged ≥66 years in Ontario, Canada, before the pandemic (April 2014 to March 2020) compared with during the pandemic (July 2020 to November 2022). Incident claim was defined as the first prescription filled for any medication in these classes. The characteristics of patients with incident prescriptions of antihyperglycemics (n=151 888) or antihypertensives (n=368 123) before the pandemic were comparable with their pandemic counterparts (antihyperglycemics, n=97 015; antihypertensives, n=146 524). Before the pandemic, monthly rates of incident prescriptions were decreasing (-0.03 per 10 000 individuals [95% CI, -0.04 to -0.01] for antihyperglycemics; -0.14 [95% CI, -0.18 to -0.10] for antihypertensives). After July 2020, monthly rates increased (postinterruption trend 0.31 per 10 000 individuals [95% CI, 0.28-0.34] for antihyperglycemics; 0.19 [95% CI, 0.14-0.23] for antihypertensives). CONCLUSIONS: Population-level increases in new antihyperglycemic and antihypertensive prescriptions during the pandemic reversed prepandemic declines and were sustained for >2 years. Our findings are concerning for current and future cardiovascular health.

From periphery to center, untold story of pure neuritic leprosy: an electrophysiological study.

BACKGROUND: Pure neuritic leprosy (PNL) is uncommon form of leprosy involving peripheral nerves. Some isolated case reports have shown imaging changes in the central nervous system (CNS) and also impairment in visual evoked potential (VEP), somatosensory evoked potential (SSEP) and brain stem auditory-evoked potentials (BAEPs) parameters in PNL, but there is lack of large study. This prospective observational study evaluates impairment in these central conduction studies among PNL patients. METHODS: We screened patients with leprosy presenting with features of neuropathy and/or thickened nerves. Patients with bacilli-positive nerve biopsies were included in the study and subjected to routine tests along with nerve conduction study (NCS), VEP, tibial SSEP and BAEPs. Parameters of these studies were analyzed based on data from previous studies. RESULTS: Of 76 patients screened for PNL 49 had positive findings in biopsy. Most of patients were male and mean age group was 46.35 ± 15.35 years. Mononeuritis multiplex was most common NCS pattern in 46.93% (23/49) patients. We found abnormal VEP in 13 out of 35 patients (37.14%). Similarly abnormal SSEP and BAEPs among 42.85% and 40% patients respectively. DISCUSSION: This study shows that in PNL significant number of patients have subclinical CNS involvement. Exact pathophysiology of CNS involvement is not known till now but study of VEP, SSEP and BAEPs parameter may help in early diagnosis of PNL.

Report of a collaborative study to establish the first Indian Pharmacopoeia reference standard for teriparatide.

A collaborative study was conducted to establish the first Indian Pharmacopoeia Reference Standard (IPRS) for teriparatide to be used in quality control testing of marketed products in compliance with the Indian Pharmacopoeia (IP) monograph. The study objective was to evaluate the candidate standard in terms of the WHO International Standard (IS) to assign its content in mg per vial terms. This study involved four laboratories from India and the candidate standard was calibrated against the WHO IS by each participant laboratory using high-performance liquid chromatography (HPLC) assay method per IP monograph. Direct calibration of the candidate standard resulted in an assigned content of 1.02 mg per vial. Based on the study results the candidate standard was judged suitable to serve as the first IPRS for teriparatide for identification and assay by HPLC.

A comprehensive review on role of Aurora kinase inhibitors (AKIs) in cancer therapeutics.

Aurora kinases (AURKs) are a family of serine /threonine protein kinases that have a crucial role in cell cycle process mainly in the event of chromosomal segregation, centrosome maturation and cytokinesis. The family consists of three members including Aurora kinase A (AURK-A), Aurora kinase B (AURK-B) and Aurora kinase C (AURK-C). All AURKs contain a conserved kinase domain for their activity but differ in their cellular localization and functions. AURK-A and AURK-B are expressed mainly in somatic cells while the expression of AURK-C is limited to germ cells. AURK-A promotes G2 to M transition of cell cycle by controlling centrosome maturation and mitotic spindle assembly. AURK-B and AURK-C form the chromosome passenger complex (CPC) that ensures proper chromosomal alignments and segregation. Aberrant expression of AURK-A and AURK-B has been detected in several solid tumours and malignancies. Hence, they have become an attractive therapeutic target against cancer. The first part of this review focuses on AURKs structure, functions, subcellular localization, and their role in tumorigenesis. The review also highlights the functional and clinical impact of selective as well as pan kinase inhibitors. Currently, >60 compounds that target AURKs are in preclinical and clinical studies. The drawbacks of existing inhibitors like selectivity, drug resistance and toxicity have also been addressed. Since, majority of inhibitors are Aurora kinase inhibitor (AKI) type-1 that bind to the active (DFGin and Cin) conformation of the kinase, this information may be utilized to design highly selective kinase inhibitors that can be combined with other therapeutic agents for better clinical outcomes.

Efficacy and safety of phospholipid nanoparticles (VBI-S) in reversing intractable hypotension in patients with septic shock: a multicentre, open-label, repeated measures, phase 2a clinical pilot trial.

Background: Since the 1990's attempts to favorably modulate nitric oxide (NO) have been unsuccessful. We hypothesized that because NO is lipophilic it would preferentially localize into intravascularly infused hydrophobic nanoparticles, thereby reducing its bioavailability and adverse effects without inhibiting its production. We aimed to determine the efficacy and safety of intravenous infusion of a fluid comprised of hydrophobic phospholipid nanoparticles (VBI-S) that reversibly absorb NO in the treatment of hypotension of patients in severe septic shock. Methods: This is a multicentre, open-label, repeated measures, phase 2a clinical pilot trial done at six hospital centers in the USA. Patients in severe septic shock were enrolled after intravenous fluid therapy had failed to raise mean arterial blood pressure (MAP) to at least the generally accepted level of 65 mmHg, requiring the use of vasopressors. The primary endpoint of this study is the proportion of patients in whom MAP increased by at least 10 mmHg. VBI-S was administered intravenously to patients as boluses of 100 ml, 200 ml, 400 ml, and 800 ml at 999 ml/min until the blood pressure goal was reached after which the infusion was stopped, and the MAP was recorded. All patients who received any volume of VBI-S were included in the primary and safety analysis. The study is registered with ClinicalTrials.gov, NCT04257136. Findings: Between February 17, 2020 and January 3, 2023, 20 eligible patients were enrolled in the study. In all 20 (100%) patients, the goal of increasing MAP by at least 10 mmHg using VBI-S was achieved (p = 0.0087, effect size = 0.654). Mean VBI-S volume required to meet the primary goal was 561.0 ± 372.3 ml. The goal of lowering vasopressor dose was also achieved (p = 0.0017). Within 48 h or less after VBI-S, there was a statistically significant improvement in oxygenation, serum creatinine, clotting variables, procalcitonin, lactic acid, and the sequential organ failure assessment (SOFA) score. At 24 h and 48 h following administration of VBI-S, 12/15 (80%) and 9/12 (75%) patients developed hyperlipidemia, respectively. No severe adverse events of VBI-S were observed, and there were no treatment-related deaths. Interpretation: These preliminary findings suggest the safety and efficacy of VBI-S in treating hypotension in patients with septic shock. However, a definitive mortality benefit cannot be demonstrated without a randomized controlled study. Funding: The Naval Medical Research Command-Naval Advanced Medical Development program via the Medical Technology Enterprise Consortium.