iNOS regulates hematopoietic stem and progenitor cells via mitochondrial signaling and is critical for bone marrow regeneration.

Hematopoietic stem cells (HSCs) replenish blood cells under steady state and on demand, that exhibit therapeutic potential for Bone marrow failures and leukemia. Redox signaling plays key role in immune cells and hematopoiesis. However, the role of reactive nitrogen species in hematopoiesis remains unclear and requires further investigation. We investigated the significance of inducible nitric oxide synthase/nitric oxide (iNOS/NO) signaling in hematopoietic stem and progenitor cells (HSPCs) and hematopoiesis under steady-state and stress conditions. HSCs contain low levels of NO and iNOS under normal conditions, but these increase upon bone marrow stress. iNOS-deficient mice showed subtle changes in peripheral blood cells but significant alterations in HSPCs, including increased HSCs and multipotent progenitors. Surprisingly, iNOS-deficient mice displayed heightened susceptibility and delayed recovery of blood progeny following 5-Fluorouracil (5-FU) induced hematopoietic stress. Loss of quiescence and increased mitochondrial stress, indicated by elevated MitoSOX and MMPhi HSCs, were observed in iNOS-deficient mice. Furthermore, pharmacological approaches to mitigate mitochondrial stress rescued 5-FU-induced HSC death. Conversely, iNOS-NO signaling was required for demand-driven mitochondrial activity and proliferation during hematopoietic recovery, as iNOS-deficient mice and NO signaling inhibitors exhibit reduced mitochondrial activity. In conclusion, our study challenges the conventional view of iNOS-derived NO as a cytotoxic molecule and highlights its intriguing role in HSPCs. Together, our findings provide insights into the crucial role of the iNOS-NO-mitochondrial axis in regulating HSPCs and hematopoiesis.

Telehealth in oncology: a cost analysis to evaluate the financial impact of implementing regional trial hubs within a phase 3 cancer clinical trial.

This cost analysis, from a societal perspective, compared the cost difference of a networked teletrial model (NTTM) with four regional hubs versus conventional trial operation at a single metropolitan specialist centre. The Australian phase 3 cancer interventional randomised controlled trial included 152 of 328 regional participants (patient enrolment 2018-2021; 6-month primary end point). The NTTM significantly reduced (AU$2155 per patient) patient travel cost and time and lost productivity.

Systemically Administered Anti-uPAR Antibody Plasma and Lung ELF Pharmacokinetics Characterized by Minimal Lung PBPK Model.

Antibody-based therapeutics have recently gained keen attention for the treatment of pulmonary indications. However, systemically administered antibody exposure in the lungs needs to be better understood and remains a topic of interest. In this study, we evaluated the exposure of two different uPAR (urokinase-type plasminogen activator receptor) targeting full-length monoclonal IgGs in plasma and lung epithelial lining fluid (ELF) of mice after IP and IV administration. Antibody AK17 exhibited linear pharmacokinetics (PK) in plasma and ELF at 3 and 30 mg/kg single IV dose. The average plasma and ELF half-lives for AK17 and AK21 ranged between ~321-411 h and ~230-345 h, respectively, indicating sustained systemic and lung exposure of antibodies. The average ELF to the plasma concentration ratio of antibodies was ~0.01 and ~0.03 with IP and IV dosing, respectively, over 2 weeks post single dose. We simultaneously characterized plasma and ELF PK of antibody in mice by developing a minimal lung PBPK model for antibody. This model reasonably captured the plasma and ELF PK data while estimating three parameters. The model accounts for the convective transport of antibody into the tissues via blood and lymph flow. FcRn-mediated transcytosis was incorporated into the model for antibody distribution across the lung epithelial barrier. This model serves as a platform to predict the pulmonary PK of systemically administered antibodies and to support optimal dose selection for desired exposure in the lungs as the site of action.

Level and Trend of Child Health and Nutrition Status in Nepal: Evidence from Demographic and Health Survey (1996-2016).

BACKGROUND: Child health and nutrition are key indicators of the country's socioeconomic development and quality of life. The purpose of the paper was to examine the level, trend, and socio-demographic differences of selected child health and nutrition indicators and to provide policy recommendations for improvement. METHODS: Desk review was conducted to compile secondary information on child health and nutrition status published in the Nepal Demographic and Health Survey reports prepared by Ministry of Health and Population from 1996 to 2016. Trend lines, bar diagram, and GIS maps were prepared to study and present the findings. RESULTS: A substantial decrease in under-five mortality, from 118 to 39 (67% point decline) and neonatal mortality, from 50 to 21 (58% point decline) deaths per 1000 live births, was noted between 1996 and 2016. Full immunization coverage decreased from 87% in 2011 to 78% in 2016. 36% of children under the age of five were stunted, 25% were underweight, and 10% were wasted in 2016. Boys were more likely to receive treatment for diarrhoea (72%), compared to girls (56%). The majority of the children (74%) had their acute respiratory infections managed at private medical centers. Child health and nutritional status differed by geographic regions, being better in Gandaki and Bagmati and poor in Karnali and Madesh. Overall health and nutrition status of children were better among educated, and wealthier families. CONCLUSIONS: To further reduce childhood mortality and reach the targets for the Sustainable Development Goal, targeted interventions must be implemented to improve immunization coverage plus health and nutritional status among disadvantaged populations.

Risk-Directed Ambulatory Thromboprophylaxis in Lung and Gastrointestinal Cancers: The TARGET-TP Randomized Clinical Trial.

Importance: Thromboprophylaxis for individuals receiving systemic anticancer therapies has proven to be effective. Potential to maximize benefits relies on improved risk-directed strategies, but existing risk models underperform in cohorts with lung and gastrointestinal cancers. Objective: To assess clinical benefits and safety of biomarker-driven thromboprophylaxis and to externally validate a biomarker thrombosis risk assessment model for individuals with lung and gastrointestinal cancers. Design, Setting, and Participants: This open-label, phase 3 randomized clinical trial (Targeted Thromboprophylaxis in Ambulatory Patients Receiving Anticancer Therapies [TARGET-TP]) conducted from June 2018 to July 2021 (with 6-month primary follow-up) included adults aged 18 years or older commencing systemic anticancer therapies for lung or gastrointestinal cancers at 1 metropolitan and 4 regional hospitals in Australia. Thromboembolism risk assessment based on fibrinogen and d-dimer levels stratified individuals into low-risk (observation) and high-risk (randomized) cohorts. Interventions: High-risk patients were randomized 1:1 to receive enoxaparin, 40 mg, subcutaneously daily for 90 days (extending up to 180 days according to ongoing risk) or no thromboprophylaxis (control). Main Outcomes and Measures: The primary outcome was objectively confirmed thromboembolism at 180 days. Key secondary outcomes included bleeding, survival, and risk model validation. Results: Of 782 eligible adults, 328 (42%) were enrolled in the trial (median age, 65 years [range, 30-88 years]; 176 male [54%]). Of these participants, 201 (61%) had gastrointestinal cancer, 127 (39%) had lung cancer, and 132 (40%) had metastatic disease; 200 (61%) were high risk (100 in each group), and 128 (39%) were low risk. In the high-risk cohort, thromboembolism occurred in 8 individuals randomized to enoxaparin (8%) and 23 control individuals (23%) (hazard ratio [HR], 0.31; 95% CI, 0.15-0.70; P = .005; number needed to treat, 6.7). Thromboembolism occurred in 10 low-risk individuals (8%) (high-risk control vs low risk: HR, 3.33; 95% CI, 1.58-6.99; P = .002). Risk model sensitivity was 70%, and specificity was 61%. The rate of major bleeding was low, occurring in 1 participant randomized to enoxaparin (1%), 2 in the high-risk control group (2%), and 3 in the low-risk group (2%) (P = .88). Six-month mortality was 13% in the enoxaparin group vs 26% in the high-risk control group (HR, 0.48; 95% CI, 0.24-0.93; P = .03) and 7% in the low-risk group (vs high-risk control: HR, 4.71; 95% CI, 2.13-10.42; P < .001). Conclusions and Relevance: In this randomized clinical trial of individuals with lung and gastrointestinal cancers who were stratified by risk score according to thrombosis risk, risk-directed thromboprophylaxis reduced thromboembolism with a desirable number needed to treat, without safety concerns, and with reduced mortality. Individuals at low risk avoided unnecessary intervention. The findings suggest that biomarker-driven, risk-directed primary thromboprophylaxis is an appropriate approach in this population. Trial Registration: ANZCTR Identifier: ACTRN12618000811202.

Discovery of LNP1892: A Precision Calcimimetic for the Treatment of Secondary Hyperparathyroidism.

The calcium sensing receptor (CaSR) plays an important role in maintaining calcium homeostasis. The use of calcimimetic cinacalcet has been established to activate CaSR and normalize hypercalcemia. However, cinacalcet has limitations due to its high cLogP and pKa. A systematic optimization of cinacalcet to reduce its cLogP and pKa yielded compound 23a (LNP1892). Compound 23a showed excellent potency and a favorable pharmacokinetics profile, and lacked the liabilities of cinacalcet, making it a highly differentiated precision calcimimetic. In adenine-diet-induced chronic kidney disease (CKD) models, 23a demonstrated robust and dose-dependent efficacy, as measured by plasma parathyroid hormone (PTH) levels. It also showed an excellent safety profile in animal studies. Phase 1 clinical trials with 23a in healthy volunteers confirmed its excellent safety, tolerability, and effectiveness in lowering PTH levels in a dose-dependent manner, without causing symptomatic hypocalcaemia. Encouraged by these promising results, LNP1892 was taken to a Phase 2 study in CKD patients.

Zinc Alpha 2 Glycoprotein as an Early Biomarker of Diabetic Nephropathy in Type 2 Diabetes Mellitus Patients.

Background and objectives Microalbuminuria is an early sign of diabetic nephropathy (DN). However, pathological abnormalities occur before the onset of microalbuminuria. Renal impairment progresses in about 50% of cases in type 2 diabetes mellitus (T2DM) without significant albuminuria. Diabetes mellitus (DM) is linked with obesity, metabolic syndrome, and lifestyle changes, where adipokines play an important role. Zinc alpha 2 glycoprotein (ZAGP) is an adipokine, and in this study, it was assessed as a potential biomarker for early DN as well as its progression. Materials and methods This study was a cross-sectional case-control study conducted at a tertiary hospital in northern India. T2DM patients aged 18-65 years old were included in the study and were divided into four groups based on their albuminuria level. This study included 160 participants, with 40 participants in each group. Group I included healthy volunteers, while Groups II, III, and IV were normoalbuminuric, microalbuminuric, and macroalbuminuric diabetic patients, respectively. The groups were evaluated for demographic variables, biochemical parameters, urine albumin-creatinine ratio (UACR), and serum ZAGP. Data between the groups were compared statistically. Results This study included 160 participants, with 40 participants in each group. There was a significant difference between the groups based on the serum ZAGP (p<0.001). Serum ZAGP was significantly negatively correlated with serum creatinine, glycosylated hemoglobin (HbA1c), serum cholesterol, serum triglyceride, low-density lipoprotein (LDL) cholesterol, and UACR. ZAGP was positively correlated with the estimated glomerular filtration rate (eGFR). Conclusion The present study showed that ZAGP was an early biomarker of diabetic nephropathy, and its value decreased as DN progressed. It also suggested that ZAGP, an adipokine, has an anti-inflammatory mechanism of action and its depletion worsens the disease.

Birth registration in Nepal: An assessment of progress based on two national surveys.

Birth registration, an essential component of the civil registration system, is expected to be complete and universal. This study assesses the progress made in recent years and identifies gaps in birth registration in Nepal. Data from the Multiple Indicator Cluster Surveys undertaken in 2014 and 2019 are used for the analysis. The two surveys included a total of 12,007 children under five years of age living with their mothers at the time of the surveys. The survey respondents were 11,821 mothers and 186 caretakers (in the case of those without mothers) of the children. The variations in the proportion of births registered among various subgroups of the children are assessed by performing bivariate analysis and binary logistic regression. Birth registration increased considerably, from 58% (95% CI: 57-59%) in 2014 to 77% (95% CI: 76-78%) in 2019. Several of the disparities between and among the various population subgroups that were evident in the 2014 survey had been considerably reduced or eliminated by 2019. The disparities in registration between boys and girls attenuated over time. Although birth registration increased for all children (ages 0-59 months old), infants still had comparatively lower levels of registration. The relatively disadvantaged provinces showed significant progress between the two survey periods. Considerable and significant progress has been made in birth registration in recent years. However, achieving universal and complete birth registration would require sustaining recent achievements and applying proven strategic interventions to ensure the inclusion of the unregistered births.

BND-22, a first-in-class humanized ILT2-blocking antibody, promotes antitumor immunity and tumor regression.

BACKGROUND: Cancer immunotherapy has revolutionized cancer treatment. However, considering the limited success of immunotherapy to only some cancer types and patient cohorts, there is an unmet need for developing new treatments that will result in higher response rates in patients with cancer. Immunoglobulin-like transcript 2 (ILT2), a LILRB family member, is an inhibitory receptor expressed on a variety of immune cells including T cells, natural killer (NK) cells and different myeloid cells. In the tumor microenvironment, binding of class I MHC (in particular HLA-G) to ILT2 on immune cells mediates a strong inhibitory effect, which manifests in inhibition of antitumor cytotoxicity of T and NK cells, and prevention of phagocytosis of the tumor cells by macrophages. METHODS: We describe here the development and characteristics of BND-22, a novel, humanized monoclonal antibody that selectively binds to ILT2 and blocks its interaction with classical MHC I and HLA-G. BND-22 was evaluated for its binding and blocking characteristics as well as its ability to increase the antitumor activity of macrophages, T cells and NK cells in various in vitro, ex vivo and in vivo systems. RESULTS: Collectively, our data suggest that BND-22 enhances activity of both innate and adaptive immune cells, thus generating robust and comprehensive antitumor immunity. In humanized mice models, blocking ILT2 with BND-22 decreased the growth of human tumors, hindered metastatic spread to the lungs, and prolonged survival of the tumor-bearing mice. In addition, BND-22 improved the antitumor immune response of approved therapies such as anti-PD-1 or anti-EGFR antibodies. CONCLUSIONS: BND-22 is a first-in-human ILT2 blocking antibody which has demonstrated efficient antitumor activity in various preclinical models as well as a favorable safety profile. Clinical evaluation of BND-22 as a monotherapy or in combination with other therapeutics is under way in patients with cancer. TRIAL REGISTRATION NUMBER: NCT04717375.

Reimagining India's Health System: Technology Levers for Universal Health Care.

Just as the COVID-19 pandemic highlighted the inadequacies of our current health systems and rekindled the debate around universal health care, the Lancet Citizens' Commission on Reimagining India's Health System was launched in late 2020. As a part of the commission, we articulated how technology can enable universal health care. We begin by stating the foundational values-a set of normative statements-that should underpin the use of technology in our health systems. Then, after summarising the paradigm shifts necessary to achieve citizen-centred universal health care, we articulate five 'technology levers' to enable those shifts. Finally, we describe the intersections and synergies between technology and the other pillars of health systems, namely, human resources, financing, governance and citizens' engagement.

Cathepsin S as an early biomarker for cardiovascular disease in chronic kidney disease patients / Catepsina S como um biomarcador precoce para doença cardiovascular em pacientes com doença renal crônica

Abstract Introduction: A high incidence of cardiovascular disease (CVD) events and premature mortality is observed in patients with chronic kidney disease (CKD). Thus, new biomarkers that may help predict the development of CVD in early stages of CKD are being investigated along with other traditional risk factors. Objective: To investigate cathepsin S as an early biomarker for CVD in patients with CKD. Methods: A total of 64 patients with CKD were included and classified into 2 groups: CKD patients with established CVD and CKD patients with non-established CVD. All patients were submitted to routine investigations including complete blood count, random blood sugar, glycated hemoglobin (HbA1c), serum electrolytes, urea, creatinine, total protein, total albumin, calcium total, phosphorous, uric acid, vitamin D, parathormone, lipid profile, liver function test, measurement of serum cathepsin S (Cat S), and 2D Echo of the heart. Results: The level of serum Cat S was increased in CKD patients with CVD (p <0.05) as well as in later stages of CKD (p <0.05). CVD was also more common in patients in early stage CKD. In early stages CKD, Cat S and CVD were positively correlated. Conclusion: These findings suggest that serum Cat S might be useful as an early biomarker for CVD in CKD patients.

Resumo Introdução: Uma alta incidência de eventos de doença cardiovascular (DCV) e mortalidade prematura é observada em pacientes com doença renal crônica (DRC). Assim, novos biomarcadores que podem ajudar a prever o desenvolvimento de DCV nos estágios iniciais da DRC estão sendo investigados juntamente com outros fatores de risco tradicionais. Objetivo: Investigar a catepsina S como um biomarcador precoce para DCV em pacientes com DRC. Métodos: Um total de 64 pacientes com DRC foram incluídos e classificados em 2 grupos: pacientes com DRC com DCV estabelecida e pacientes com DRC com DCV não estabelecida. Todos os pacientes foram submetidos a investigações de rotina incluindo hemograma completo, glicemia aleatória, hemoglobina glicada (HbA1C), eletrólitos séricos, ureia, creatinina, proteína total, albumina total, cálcio total, fósforo, ácido úrico, vitamina D, paratormônio, perfil lipídico, teste de função hepática, medição da catepsina S sérica (Cat S), e Eco 2D do coração. Resultados: O nível de Cat S sérica esteve aumentado em pacientes com DRC com DCV (p <0,05), bem como em estágios posteriores da DRC (p <0,05). A DCV também foi mais comum em pacientes com DRC em estágio inicial. Em estágios iniciais da DRC, a Cat S e a DCV foram positivamente correlacionadas. Conclusão: Estes achados sugerem que a Cat S sérica pode ser útil como um biomarcador precoce para DCV em pacientes com DRC.

Discovery and pre-clinical characterization of a selective PI3Kδ inhibitor, LL-00071210 in rheumatoid arthritis.

PI3Kδ plays a critical role in adaptive immune cell activation and function. Suppression of PI3Kδ has been shown to counter excessive triggering of immune responses which has led to delineating the role of this isoform in the pathophysiology of autoimmune disorders. In the current study, we have described preclinical characterization of PI3Kδ specific inhibitor LL-00071210 in various rheumatoid arthritis models. LL-00071210 displayed excellent in vitro potency in biochemical and cellular assay against PI3Kδ with IC50 values of 24.6 nM and 9.4 nM, respectively. LL-00071210 showed higher selectivity over PI3Kγ and PI3Kß as compared to available PI3K inhibitors. LL-00071210 had good stability in liver microsomes and plasma across species and showed low clearance, low-to-moderate Vss, with bioavailability of >50% in preclinical species. LL-00071210 demonstrated excellent in vivo efficacy in adjuvant-induced and collagen-induced arthritis models. Co-administration of LL-00071210 and methotrexate at subtherapeutic dose regimen in collagen induced arthritis model led to additive effects, indicating the combination potential of LL-00071210 along with available disease modifying anti-rheumatic drugs (DMARD). In conclusion, we have described a specific PI3Kδ inhibitor with ∼100-fold selectivity over other PI3K isoforms. LL-00071210 has good drug-like properties and thus warrants testing in the clinic for the treatment of autoimmune diseases.

Are drains useful in eTEP ventral hernia repairs? An AWR surgical collaborative (AWRSC) retrospective study.

BACKGROUND: Drain practices in minimally invasive retromuscular ventral hernia repairs have largely been transferred over from open surgery without significant review. We wished to evaluate the role of drains in these repairs. METHODS: Using the Abdominal Wall Reconstruction Surgical Collaborative (AWRSC) registry, patients with ventral hernias who underwent enhanced-view totally extraperitoneal (eTEP) repairs between February 2016 and September 2019 were evaluated. Patients with contamination or active infection within the surgical field, those who underwent an emergent or hybrid repair, or received a concomitant procedure were excluded. Propensity score matching based on the defect size, previous hernia repair status, and the use of posterior component separation (PCS) was used to match patients with drains to patients without drains. We evaluated 180-day outcomes in terms of SSIs, SSOs, and recurrence. RESULTS: 308 patients met the inclusion criteria. After propensity score matching, 48 patients with drains and 72 without drains were included in the analysis cohort. Those with drains were older with a greater likelihood of an incisional hernia, but were broadly similar for other relevant demographic and hernia-related variables. While there was no difference in the incidence of SSOs and SSIs between the two groups, we report a higher risk of SSOs needing procedural intervention (SSOPI) and recurrence, with a lengthened hospital stay in the cohort that received surgical drains. CONCLUSION: The use of surgical drains in "clean" eTEP repairs of ventral hernias appears to be common, with a selection bias for more complex cases. Based on our analysis, we found the use of drains was associated with longer hospital stays. The use of drains did not change the likelihood of suffering an SSI or SSO. However, the incidence of SSOPIs was higher despite the use of drains, which raises questions about their protective role in these repairs.

Assessment of antidiabetic effect of 4-HIL in type 2 diabetic and healthy Sprague Dawley rats.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia and insulin resistance. 4-hydroxyisoleucine (4-HIL) is a non-proteinogenic amino acid isolated from the fenugreek seeds and has enormous pharmacological activities. The present study was undertaken to investigate the antihyperglycemic effect of 4-HIL in streptozotocin (STZ)-induced diabetic rats. Moreover, its toxicity was evaluated in vitro and in vivo employing human embryonic kidney cells (HEK-293) and healthy rats, respectively. In experiment 1, STZ-induced diabetic male rats were subjected to an oral treatment of 4-HIL (100 mg/kg), while experiment 2 deals with the effects of 4-HIL on healthy male and female rats following oral administration. The treatment (experiment 1) declined the elevated blood glucose level, feed intake, and increased body weight(s). Additionally, blood glucose impairment was improved as observed by OGTT and IPGT tests. Pancreatic histopathology revealed mild changes in the 4-HIL group. Moreover, experiment 2 showed increased body weight, normal blood glucose levels (male-106.06 ± 7.49 mg/dl and female-100.06 ± 14.69 mg/dL), hematological parameters, and histopathological profiles in the treatment group. 4-HIL did not affect the viability of HEK-293 cells, and no signs of toxicity were observed in healthy rats. Therefore, the study concludes that 4-HIL has potential antihyperglycemic activity without any toxic effects.

Cathepsin S as an early biomarker for cardiovascular disease in chronic kidney disease patients.

INTRODUCTION: A high incidence of cardiovascular disease (CVD) events and premature mortality is observed in patients with chronic kidney disease (CKD). Thus, new biomarkers that may help predict the development of CVD in early stages of CKD are being investigated along with other traditional risk factors. OBJECTIVE: To investigate cathepsin S as an early biomarker for CVD in patients with CKD. METHODS: A total of 64 patients with CKD were included and classified into 2 groups: CKD patients with established CVD and CKD patients with non-established CVD. All patients were submitted to routine investigations including complete blood count, random blood sugar, glycated hemoglobin (HbA1c), serum electrolytes, urea, creatinine, total protein, total albumin, calcium total, phosphorous, uric acid, vitamin D, parathormone, lipid profile, liver function test, measurement of serum cathepsin S (Cat S), and 2D Echo of the heart. RESULTS: The level of serum Cat S was increased in CKD patients with CVD (p <0.05) as well as in later stages of CKD (p <0.05). CVD was also more common in patients in early stage CKD. In early stages CKD, Cat S and CVD were positively correlated. CONCLUSION: These findings suggest that serum Cat S might be useful as an early biomarker for CVD in CKD patients.

STimulator of INterferon Genes Agonism Accelerates Antitumor Activity in Poorly Immunogenic Tumors.

The innate immune agonist STING (STimulator of INterferon Genes) binds its natural ligand 2'3'-cGAMP (cyclic guanosine-adenosine monophosphate) and initiates type I IFN production. This promotes systemic antigen-specific CD8+ T-cell priming that eventually provides potent antitumor activity. To exploit this mechanism, we synthesized a novel STING agonist, MSA-1, that activates both mouse and human STING with higher in vitro potency than cGAMP. Following intratumoral administration of MSA-1 to a panel of syngeneic mouse tumors on immune-competent mice, cytokine upregulation and its exposure were detected in plasma, other tissues, injected tumors, and noninjected tumors. This was accompanied by effective antitumor activity. Mechanistic studies in immune-deficient mice suggested that antitumor activity of intratumorally dosed STING agonists is in part due to necrosis and/or innate immune responses such as TNF-α activity, but development of a robust adaptive antitumor immunity is necessary for complete tumor elimination. Combination with PD-1 blockade in anti-PD-1-resistant murine models showed that MSA-1 may synergize with checkpoint inhibitors but can also provide superior tumor control as a single agent. We show for the first time that potent cyclic dinucleotides can promote a rapid and stronger induction of the same genes eventually regulated by PD-1 blockade. This may have contributed to the relatively early tumor control observed with MSA-1. Taken together, these data strongly support the development of STING agonists as therapy for patients with aggressive tumors that are partially responsive or nonresponsive to single-agent anti-PD-1 treatment by enhancing the anti-PD-1 immune profile.

Internet of Medical Things-Based Secure and Energy-Efficient Framework for Health Care.

The Internet of Medical Things (IoMT) is a collection of medical equipment and software that can help patients get better care. The purpose of this study is to improve the security of data collected through remote health monitoring of patients utilizing Constrained Application Protocol (CoAP). Asymmetric cryptography techniques may be used to assure the security of such sensor networks. For communication between different IoMT devices and a remote server, the safe CoAP is compatible with the Datagram Transport Layer Security (DTLS) protocol for creating a secure session using existing algorithms such as Lightweight Establishment of Secure Session. The DTLS layer of CoAP, in contrast, has shortcomings in key control, session establishment, and multicast message exchange. As a consequence, for IoMT communication, the creation of an efficient protocol for safe CoAP session establishment is needed. Thus, to solve the existing problems related to key management and multicast security in CoAP, we have proposed an efficient and secure communication technique to establish a secure session key between IoMT devices and distant servers using lightweight Energy-Efficient and Secure CoAP Elliptic Curve Cryptography (E2SCEC2). The advantage of using E2SCEC2 over other identification methods such as Rivest-Shamir-Adleman (RSA) is its compact key size, which allows it to use a smaller key size. This article also compares these algorithms on parameters such as time spent generating keys, signature generation, and verification of E2SCEC2 and RSA algorithms, as well as energy consumption and radio duty cycle, to see if they are compatible in constrained environments.

Phase III, Randomized, Double-blind, Placebo controlled trial of Efficacy, Safety and Tolerability of Antiviral drug Umifenovir vs Standard care of therapy in non-severe COVID-19 patients.

OBJECTIVE: To test efficacy, safety and tolerability of Umifenovir in non-severe COVID-19 adult patients. METHODS: We carried out randomized, double-blind, placebo-controlled, multicenter, phase III trials involving adult (18-75 years), non-severe COVID19 patients, randomized 1:1 on placebo or Umifenovir (800 mg BID, maximum 14 days) respectively along with standard-of-care. The primary endpoint for Asymptotic-mild patients was time to nasopharyngeal swab RT-PCR test negativity. For Moderate patients, the average change in the ordinal scale from the baseline scores on the eight-point WHO ordinal scale was assessed. RESULTS: 132 patients were recruited between 3rd October to 28th April 2021, of which 9 discontinued due to various reasons. In Mild-asymptomatic patients (n=82), we found that 73% patients in the Umifenovir arm were RT-PCR negative, while 40% patients in the placebo arm were negative (P=0.004) on day 5. However, in the moderate group (n=41), the WHO scores for the Umifenovir arm was not statistically significant (P=0.125 on day 3), while it was statistically significant in the Mild-asymptomatic group (P=0.019 on day 5). CONCLUSION: Umifenovir meets the primary and secondary endpoint criteria and exhibits statistically significant efficacy for Mild-asymptomatic patients. It is efficacious, safe and well-tolerated at the tested dosage of 800mg BID, maximum 14 days.