Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Added advantage of ayurvedic management in a series of 100 cases of osteoarthritis of the knee joint: a shared experience between Orthopaedic and Ayurvedic Faculty

Osteoarthritis of the knee joint is a disease due to the uncoupling of balance between cartilage degeneration and regeneration in the elderly, causing knee joint pain, deformity and limp. About half of the population after the fifth decade of life have symptoms of osteoarthritis of the knee. The treatment of osteoarthritis varies from conservative to operative procedures. As yet, no long-term definitive conservative management has been described. We compared the Results of osteoarthritis among 100 patients in the Orthopaedic outpatient department who either underwent (42 patients) or did not undergo (58 patients) added ayurvedic panchakarma (snehan and swedan) therapy. Patients′ visual anologue scores and satisfaction scores were assessed before the treatment and after 2 and 4 weeks. Patients with early to moderate grade of osteoarthritis treated with added ayurvedic therapy showed better improvment in terms of pain and mobilization compared with the patients treated with analgesics only

Enhancing Gene-Knockdown Efficiency of Poly(<i>N</i>‑isopropylacrylamide) Nanogels

Polo-like-kinase 1 (PLK1), which is a serine–threonine protein kinase overexpressed in cancer cells, is known to regulate tumor growth and have recently gathered attention as a target gene for RNA interference because of the poor bioavailability and nonspecificity of the available inhibitors. However, the lower transfection efficiency of siRNA and its poor stability in biological mileu necessitate the need of efficient siRNA delivery systems. Here, we report efficacious polymeric nanoparticles for the delivery of PLK1 siRNA in mammalian cancer cells. <i>N</i>-Isopropylacrylamide (NIPAm) and <i>N</i>-isopropylmethacrylamide-<i>co</i>-NIPAm nanogels were synthesized and modified using poly-ε-lysine. Furthermore, their ability to induce gene silencing was investigated by flow cytometry and real-time polymerase chain reaction, and the silencing efficiency observed was related to the polymer composition and its effect on the gene loading and protection ability and the endosomal escape capability. This study attempts to leverage the understanding of the cell–material interaction, thus, addressing the bottlenecks of siRNA delivery for enhancing the efficacy of the poly­(<i>N</i>-isopropylacrylamide)-based delivery vehicle

Bilateral submandibular swelling diagnosed as tuberculous lymphadenitis in an asymptomatic patient: A rare case report

In India, tuberculosis (TB) is a prevalent systemic disease and number of people who die with TB is increasing year by year. TB can be life-threatening, and there is a high mortality rate of systemic infection with TB. Although extrapulmonary TB (EPTB) is a rare form of TB, its prevalence is increasing day-by-day. Reported here is a case of a 28-year-old female patient with a painless swelling bilaterally in the submandibular region. She was diagnosed with bilateral submandibular tuberculous lymphadenitis. Tuberculous lymphadenitis, when occurring in the cervical region, continues to be a common cause of EPTB. Thorough knowledge of this condition is important as it can help in early diagnosis leading to prompt treatment of the patient and prevent further complications

Core–Shell Nanoparticles as an Efficient, Sustained, and Triggered Drug-Delivery System

One of the challenges in designing a successful drug-delivery vehicle is the control over drug release. Toward this, a number of multifunctional nanoparticles with multiple triggers and complex chemistries have been developed. To achieve an efficient and maximum therapeutic effect, a trigger dependent drug-delivery system with sustained release is desirable. In this paper, we report the use of a combination of thermoresponsive gold core and polymeric shell nanoparticles that can provide a sustained, triggered release of doxorubicin, making the system more efficient compared to individual nanoparticles. The selection of the system was dependent on the best trigger applicable in biological systems and a component responsive to that trigger. Because of the best tissue penetration depth observed for radiofrequency (rf), we chose rf as a trigger. Whereas the gold nanoparticles (AuNPs) provided hyperthermia trigger on exposure to rf fields, the thermoresponsiveness was endowed by poly­(<i>N</i>-isopropylacrylamide) (pNIPAm)-based polymer shells. AuNPs with three different compositions of shells, only pNIPAm and p­(NIPAm-<i>co</i>-NIPMAm) with the ratio of NIPAm/<i>N</i>-(isopropylmethacrylamide) (NIPMAm) 1:1 (pNIPMAm₅₀) and 1:3 (pNIPMAm₇₅), were synthesized. We observed that the polymer coating on the AuNPs did not affect the heating efficiency of AuNPs by rf and exhibited a temperature-dependent release of the chemotherapeutic drug, doxorubicin. The nanoparticles were biocompatible, stable in biologically relevant media, and were able to show a burst as well as a sustained release, which was rf-dependent. Interestingly, we observed that when HeLa cells were treated with doxorubicin-loaded gold core–polymeric shell NPs and exposed to rf for varying times, the mixture of the two polymeric shell nanoparticles induced more cell death as compared to the cells treated with single nanoparticles, suggesting that such multi-nanoparticle systems can be more efficacious delivery systems instead of a single multicomponent system

Enhancing Cubosome Functionality by Coating with a Single Layer of Poly-ε-lysine

We report the preparation and characterization of monoolein cubosomes that can be easily surface modified through adsorption of a single layer of cationic poly-ε-lysine. Poly-ε-lysine coated cubosomes show remarkable stability in serum solution, are nontoxic and, are readily internalized by HeLa cells. The poly-ε-lysine coating provides chemical handles for further bioconjugation of the cubosome surface. We also demonstrate that the initial release rate of a hydrophilic drug, Naproxen sodium, from the cubosomes is retarded with just a single layer of polymer. Interestingly, cubosomes loaded with Naproxen sodium, recently shown to have anticancer properties, cause more apoptosis in HeLa cells when compared to free unencapsulated drug

Myosin Vb Mediated Plasma Membrane Homeostasis Regulates Peridermal Cell Size and Maintains Tissue Homeostasis in the Zebrafish Epidermis

<div><p>The epidermis is a stratified epithelium, which forms a barrier to maintain the internal milieu in metazoans. Being the outermost tissue, growth of the epidermis has to be strictly coordinated with the growth of the embryo. The key parameters that determine tissue growth are cell number and cell size. So far, it has remained unclear how the size of epidermal cells is maintained and whether it contributes towards epidermal homeostasis. We have used genetic analysis in combination with cellular imaging to show that zebrafish <i>goosepimples/myosin Vb</i> regulates plasma membrane homeostasis and is involved in maintenance of cell size in the periderm, the outermost epidermal layer. The decrease in peridermal cell size in Myosin Vb deficient embryos is compensated by an increase in cell number whereas decrease in cell number results in the expansion of peridermal cells, which requires <i>myosin Vb (myoVb)</i> function. Inhibition of cell proliferation as well as cell size expansion results in increased lethality in larval stages suggesting that this two-way compensatory mechanism is essential for growing larvae. Our analyses unravel the importance of Myosin Vb dependent cell size regulation in epidermal homeostasis and demonstrate that the epidermis has the ability to maintain a dynamic balance between cell size and cell number.</p></div