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Community engagement is vital to the development of people-centered, successful vaccination programs. The diverse Vaccination Acceptance Research Network (VARN) community brings together interdisciplinary professionals from across the immunization ecosystem who play a crucial role in vaccination acceptance, demand, and delivery. Over the course of the VARN2023 conference, researchers and practitioners alike shared ideas and experiences focused on strategies and approaches to building trust between communities and health systems to increase equity in vaccination. Health professionals and community members must have equal value in the design and delivery of community-centered immunization services, while key vaccination decision-makers must also consider community experiences, concerns, and expertise in program design and policymaking. Therefore, strategies for community engagement and cultivating trust with communities are crucial for the success of any immunization program. Furthermore, health workers need additional skills, support, and resources to effectively communicate complex information about immunization, including effective strategies for countering misinformation. This article summarizes three skills-building sessions offered at the VARN2023 conference, focused on human-centered design, motivational interviewing, and engaging with journalists to leverage the voices of communities. These sessions offered practical, evidence-based tools for use across geographic and social settings that can be used by practitioners, researchers, and other stakeholders to increase vaccination demand and uptake in their communities.
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Promoting vaccine acceptance and demand is an essential, yet often underrecognized component of ensuring that everyone has access to the full benefits of immunization. Convened by the Sabin Vaccine Institute, the Vaccination Acceptance Research Network (VARN) is a global network of multidisciplinary stakeholders driving strengthened vaccination acceptance, demand, and delivery. VARN works to advance and apply social and behavioral science insights, research, and expertise to the challenges and opportunities facing vaccination decision-makers. The second annual VARN conference, When Communities Lead, Global Immunization Succeeds, was held June 13-15, 2023, in Bangkok, Thailand. VARN2023 provided a space for the exploration and dissemination of a growing body of evidence, knowledge, and practice for driving action across the vaccination acceptance, demand, and delivery ecosystem. VARN2023 was co-convened by Sabin and UNICEF and co-sponsored by Gavi, the Vaccine Alliance. VARN2023 brought together 231 global, regional, national, sub-national, and community-level representatives from 47 countries. The conference provided a forum to share learnings and solutions from work conducted across 40+ countries. This article is a synthesis of evidence-based insights from the VARN2023 Conference within four key recommendations: (1) Make vaccine equity and inclusion central to programming to improve vaccine confidence, demand, and delivery; (2) Prioritize communities in immunization service delivery through people-centered approaches and tools that amplify community needs to policymakers, build trust, and combat misinformation; (3) Encourage innovative community-centric solutions for improved routine immunization coverage; and (4) Strengthen vaccination across the life course through building vaccine demand, service integration, and improving the immunization service experience. Insights from VARN can be applied to positively impact vaccination acceptance, demand, and uptake around the world.
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Recent literature reports highlight the importance of the renal outer medullary potassium (ROMK) channel in renal sodium and potassium homeostasis and emphasize the potential impact that ROMK inhibitors could have as a novel mechanism diuretic in heart failure patients. A series of piperazine-based ROMK inhibitors were designed and optimized to achieve excellent ROMK potency, hERG selectivity, and ADME properties, which led to the identification of compound 28 (BMS-986308). BMS-986308 demonstrated efficacy in the volume-loaded rat diuresis model as well as promising in vitro and in vivo profiles and was therefore advanced to clinical development.
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Insuficiencia Cardíaca , Bloqueadores de los Canales de Potasio , Animales , Insuficiencia Cardíaca/tratamiento farmacológico , Humanos , Ratas , Bloqueadores de los Canales de Potasio/uso terapéutico , Bloqueadores de los Canales de Potasio/farmacología , Bloqueadores de los Canales de Potasio/química , Bloqueadores de los Canales de Potasio/farmacocinética , Bloqueadores de los Canales de Potasio/síntesis química , Relación Estructura-Actividad , Canales de Potasio de Rectificación Interna/antagonistas & inhibidores , Canales de Potasio de Rectificación Interna/metabolismo , Descubrimiento de Drogas , Diuresis/efectos de los fármacos , Piperazinas/farmacología , Piperazinas/química , Piperazinas/uso terapéutico , Piperazinas/síntesis química , Piperazinas/farmacocinética , Masculino , Ratas Sprague-DawleyRESUMEN
Nanosized mesoporous silica has emerged as a promising flexible platform delivering siRNA for cancer treatment. This ordered mesoporous nanosized silica provides attractive features of well-defined and tunable porosity, structure, high payload, and multiple functionalizations for targeted delivery and increasing biocompatibility over other polymeric nanocarriers. Moreover, it also overcomes the lacunae associated with traditional administration of drugs. Chemically modified porous silica matrix efficiently entraps siRNA molecules and prevents their enzymatic degradation and premature release. This Review discusses the synthesis of silica using the sol-gel approach and the advantages with different silica mesostructure. Herein, the factors affecting the synthesis of silica at nanometer scale, shape, porosity and nanoparticle surface modification are also highlighted to attain the desired nanostructured silica carriers. Additional emphasis is given to chemically modified silica delivering siRNA, where the silica nanoparticle surface was modified with different chemical moieties such as amine modified with (3-aminoropyl) triethoxysilane, polyethylenimine, chitosan, poly(ethylene glycol), and cyclodextrin polymer modification to attain high therapeutic loading, improved dispersibility and biocompatibility. Upon systemic administration, ordered mesoporous nanosized silica encounters blood cells, immune cells, and organs mainly of the reticuloendothelial system (RES). Thereby, biocompatibility and biodistribution of silica based nanocarriers are deliberated to design principles for smart and efficacious nanostructured silica-siRNA carriers and their clinical trial status. This Review further reports the future scopes and challenges for developing silica nanomaterial as a promising siRNA delivery vehicle demanding FDA approval.
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Neoplasias , ARN Interferente Pequeño , Dióxido de Silicio , Dióxido de Silicio/química , ARN Interferente Pequeño/uso terapéutico , ARN Interferente Pequeño/administración & dosificación , ARN Interferente Pequeño/química , Humanos , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Porosidad , Nanopartículas/química , Nanopartículas/uso terapéutico , Animales , Portadores de Fármacos/químicaRESUMEN
Pharmaceuticals, recognized for their life-saving potential, have emerged as a concerning class of micropollutants in the environment. Even at minute concentrations, chronic exposure poses a significant threat to ecosystems. Various pharmaceutically active micropollutants (PhAMP), including antibiotics, analgesics, and hormones, have been detected in underground waters, surface waters, seawater, sewage treatment plants, soils, and activated sludges due to the absence of standardized regulations on pharmaceutical discharge. Prolonged exposureof hospital waste and sewage treatment facilities is linked to the presence of antibiotic-resistant bacteria. Conventional water treatment methods prove ineffective, prompting the use of alternative techniques like photolysis, reverse osmosis, UV-degradation, bio-degradation, and nano-filtration. However, commercial implementation faces challenges such as incomplete removal, toxic sludge generation, high costs, and the need for skilled personnel. Research gaps include the need to comprehensively identify and understand various types of pharmaceutically active micropollutants, investigate their long-term ecological impact, develop more sensitive monitoring techniques, and explore integrated treatment approaches. Additionally, there is a gap in understanding the socio-economic implications of pharmaceutical pollution and the efficacy of public awareness campaigns. Future research should delve into alternative strategies like phagotherapy, vaccines, and natural substance substitutes to address the escalating threat of pharmaceutical pollution.
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Chemotherapy and immunotherapy are two important modalities in cancer management. However, due to multiple reasons, a monotherapy is only partially effective. Hence, if used concurrently in targeted and stimuli-responsive manner, it could have been superior therapeutically. To facilitate co-delivery of chemotherapeutic and immunotherapeutic agent to the target cancer cells, engineered nanoparticles, i.e., a pH-responsive polymer PLGA-coated magnetic silica nanoparticles (Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs) encapsulating paclitaxel (PTX) and siRNA against programmed cell death ligand-1 (PD-L1) are synthesized and characterized. Developed nanoparticles demonstrated pH-sensitive sustained drug release up to 10 days. In vitro 4T1 cell line studies showed efficient cellular uptake, PD-L1 gene downregulation, and apoptosis. Further, in vivo efficacy studies carried out in the mice model demonstrated a significant reduction of tumor growth following treatment with dual-Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs as compared with monotherapy with Fe3O4-SiO2-PLGA-PDA-PTX NPs. The high therapeutic efficacy observed with dual-Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs was mainly due to the cytotoxic effect of PTX combined with targeted silencing of the gene of interest, i.e., PD-L1, which in turn improve CD8+ T cell-mediated cancer cell death as evident with increased proliferation of CD8+ T cells in co-culture experiments. Thereby, dual-Fe3O4-SiO2-PLGA-PDA-PTX-siRNA NPs may have a promising anti-cancer treatment potential against breast cancer; however, the beneficial effects of dual loading of PTX + PD-L1 siRNA may be corroborated against other cancer models such as lung and colorectal cancer models as well as in clinical trials.
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As a result of our continued efforts to pursue Gal-3 inhibitors that could be used to fully evaluate the potential of Gal-3 as a therapeutic target, two novel series of benzothiazole derived monosaccharides as potent (against both human and mouse Gal-3) and orally bioavailable Gal-3 inhibitors, represented by 4 and 5, respectively, were identified. These discoveries were made based on proposals that the benzothiazole sulfur atom could interact with the carbonyl oxygen of G182/G196 in h/mGal-3, and that the anomeric triazole moiety could be modified into an N-methyl carboxamide functionality. The interaction between the benzothiazole sulfur and the carbonyl oxygen of G196 in mGal-3 was confirmed by an X-ray co-crystal structure of early lead 9, providing a rare example of using a S···O binding interaction for drug design. It was found that for both the series, methylation of 3-OH in the monosaccharides caused no loss in h & mGal-3 potencies but significantly improved permeability of the molecules.
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Galectina 3 , Monosacáridos , Animales , Humanos , Ratones , Benzotiazoles/química , Benzotiazoles/farmacología , Diseño de Fármacos , Galectina 3/antagonistas & inhibidores , Galectinas/antagonistas & inhibidores , Monosacáridos/química , Monosacáridos/farmacología , Oxígeno , AzufreRESUMEN
Immunization has one of the highest coverage levels of any health intervention, yet there remain zero-dose children, defined as those who do not receive any routine immunizations. There were 18.2 million zero-dose children in 2021, and as they accounted for over 70% of all underimmunized children, reaching zero-dose children will be essential to meeting ambitious immunization coverage targets by 2030. While certain geographic locations, such as urban slum, remote rural, and conflict-affected settings, may place a child at higher risk of being zero-dose, zero-dose children are found in many places, and understanding the social, political, and economic barriers they face will be key to designing sustainable programs to reach them. This includes gender-related barriers to immunization and, in some countries, barriers related to ethnicity and religion, as well as the unique challenges associated with reaching nomadic, displaced, or migrant populations. Zero-dose children and their families face multiple deprivations related to wealth, education, water and sanitation, nutrition, and access to other health services, and they account for one-third of all child deaths in low- and middle-income countries. Reaching zero-dose children and missed communities is therefore critical to achieving the Sustainable Development Goals commitment to "leave no one behind".
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Determining the purity of deuterium labelled compounds is important due to the increasing use of these compounds in mass spectrometry (MS) based quantitative analyses for targeting metabolic flux, reducing toxicity, confirming reaction mechanisms during synthesis, predicting enzyme mechanisms, and enhancing the efficacy of drugs, in quantitative proteomics, and also as internal standards. In the present study, a strategy using liquid chromatography electrospray ionization high resolution mass spectrometry (LC-ESI-HR-MS) and nuclear magnetic resonance (NMR) spectroscopy was proposed to determine the isotopic enrichment and structural integrity of deuterium labelled compounds. The proposed strategy involves recording full scan MS, extracting and integrating isotopic ions, and calculating the isotopic enrichment of the desired labelled compounds. NMR analysis confirms structural integrity or positions of labelled atoms and can provide insights into the relative percent isotopic purity. This strategy was used to evaluate the isotopic enrichment and structural integrity of in-house synthesized compounds as well as a series of commercially available deuterium labelled compounds. The % isotopic purity for labelled compounds of a benzofuranone derivative (BEN-d2), tamsulosin-d4 (TAM-d4), oxybutynin-d5 (OXY-d5), eplerenone-d3 (EPL-d3), and propafenone-d7 (PRO-d7) was calculated and found to be 94.7, 99.5, 98.8, 99.9, and 96.5, respectively. All the samples were run in triplicate and the results were observed to be reproducible.
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Imagen por Resonancia Magnética , Espectrometría de Masa por Ionización de Electrospray , Deuterio/química , Espectroscopía de Resonancia Magnética , Cromatografía Liquida/métodosRESUMEN
Galectin-3 (Gal-3), a member of the ß-galactoside-binding protein family, is implicated in a wide variety of human diseases. Identification of Gal-3 inhibitors with the right combination of potency (against both human and mouse Gal-3) and pharmacokinetic properties to fully evaluate the potential of Gal-3 for therapeutic intervention has been a major challenge due to the characteristics of its binding pocket: high hydrophilicity and key structural differences between human Gal-3 and the mouse ortholog. We report the discovery of a novel series of monosaccharide-based, highly potent, and orally bioavailable inhibitors of human and mouse Gal-3. The novel monosaccharide derivatives proved to be selective for Gal-3, the only member of the chimeric type of galectins, over Gal-1 and Gal-9, representative of the prototype and tandem-repeat type of galectins, respectively. The proposed binding mode for the newly identified ligands was confirmed by an X-ray cocrystal structure of a representative analogue bound to Gal-3 protein.
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Galectina 3 , Monosacáridos , Animales , Galectina 3/metabolismo , Galectinas , Humanos , Ligandos , RatonesRESUMEN
GSK3640254 is an HIV-1 maturation inhibitor (MI) that exhibits significantly improved antiviral activity toward a range of clinically relevant polymorphic variants with reduced sensitivity toward the second-generation MI GSK3532795 (BMS-955176). The key structural difference between GSK3640254 and its predecessor is the replacement of the para-substituted benzoic acid moiety attached at the C-3 position of the triterpenoid core with a cyclohex-3-ene-1-carboxylic acid substituted with a CH2F moiety at the carbon atom α- to the pharmacophoric carboxylic acid. This structural element provided a new vector with which to explore structure-activity relationships (SARs) and led to compounds with improved polymorphic coverage while preserving pharmacokinetic (PK) properties. The approach to the design of GSK3640254, the development of a synthetic route and its preclinical profile are discussed. GSK3640254 is currently in phase IIb clinical trials after demonstrating a dose-related reduction in HIV-1 viral load over 7-10 days of dosing to HIV-1-infected subjects.
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Fármacos Anti-VIH , VIH-1 , Triterpenos , Humanos , Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Fármacos Anti-VIH/uso terapéutico , Ácido Benzoico/química , Carbono , Triterpenos/química , Triterpenos/farmacología , Triterpenos/uso terapéuticoRESUMEN
Gender-related barriers to immunization are key targets to improve immunization coverage and equity. We used individual-level demographic and health survey data from 52 low- and middle-income countries to examine the relationship between women's social independence (measured by the Survey-based Women's emPowERment (SWPER) Global Index) and childhood immunization. The primary outcome was receipt of three doses of the diphtheria-tetanus-pertussis vaccine (DTP3) among children aged 12-35 months; we secondarily examined failure to receive any doses of DTP-containing vaccines. We summarized immunization coverage indicators by social independence tertile and estimated crude and adjusted summary measures of absolute and relative inequality. We conducted all analyses at the country level using individual data; median results across the 52 examined countries are also presented. In crude comparisons, median DTP3 coverage was 12.3 (95% CI 7.9; 16.3) percentage points higher among children of women with the highest social independence compared with children of women with the lowest. Thirty countries (58%) had a difference in coverage between those with the highest and lowest social independence of at least 10 percentage points. In adjusted models, the median coverage was 7.4 (95% CI 5.0; 9.1) percentage points higher among children of women with the highest social independence. Most countries (41, 79%) had statistically significant relative inequality in DTP3 coverage by social independence. The findings suggest that greater social independence for women was associated with better childhood immunization outcomes, adding evidence in support of gender-transformative strategies to reduce childhood immunization inequities.
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Pancreatic cancer (PC) is the primary cause of cancer death in the United States and Europe. Despite remarkable advances in the molecular understanding of PC and advances in new therapeutic approaches, PC remains a disease with a poor prognosis. Although evidence indicates that long-term smoking is a major cause of PC, the molecular pathways behind smoking-induced PC pathogenesis are not fully understood. Smoking cessation can significantly reduce the occurrence of PC. This review explores the processes underpinning the influence of smoking-related chemicals on fibrosis and inflammation and provides insight into the etiology of PC. In the future, a thorough exploration of the effects of smoking chemicals on the activity of pancreatic stem cells and then on the essential mediators of the association with cancer cells would likely yield new diagnostic targets.
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Thyroid hormones (TH) regulate growth, nervous system myelination, metabolism, and physiologic functions in nearly every organ system. Congenital hypothyroidism (CH) is one of the most common endocrinopathies in children and has potentially devastating neurologic and developmental consequences. The etiology and clinical manifestations of hypothyroidism in children differ from adults. And hence, pediatric medical care requires a detailed understanding of thyroid function and dysfunction in children. The perinatal risk factors include female sex, preterm birth, low birth weight, postmature birth, additional birth abnormalities, and being delivered in multiple births. In countries where newborn screening is practiced, CH is detected after birth through screening tests. It aids in determining the underlying cause, though some patients may be able to start treatment without these tests. Early detection and treatment prevent irreversible and permanent nervous system damage. Thus, in addition to exploring the development of CH, this article has also covered the epidemiological data, clinical aspects, and management stemming from pediatric hypothyroidism.
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Protease-activated receptor 4 (PAR4) is a G-protein coupled receptor that is expressed on human platelets and activated by the coagulation enzyme thrombin. PAR4 plays a key role in blood coagulation, and its importance in pathological thrombosis has been increasingly recognized in recent years. Herein, we describe the optimization of a series of imidazothiadiazole PAR4 antagonists to a first-in-class clinical candidate, BMS-986120 (43), and a backup clinical candidate, BMS-986141 (49). Both compounds demonstrated excellent antithrombotic efficacy and minimal bleeding time prolongation in monkey models relative to the clinically important antiplatelet agent clopidogrel and provide a potential opportunity to improve the standard of care in the treatment of arterial thrombosis.
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Agregación Plaquetaria , Trombosis , Benzofuranos , Plaquetas , Humanos , Imidazoles , Morfolinas , Receptor PAR-1 , Receptores de Trombina , Tiazoles , Trombina , Trombosis/tratamiento farmacológicoRESUMEN
A neurodegenerative disorder, Alzheimer's disease (AD), is characterized by dementia in which there is an age-related decline in cognition and higher functions. Stroke is a cerebrovascular disorder that frequently presents in old age and is a known risk factor for AD development. However, the association that AD can be a risk factor for stroke is not well-studied. This review article compiled various studies that pointed out the association between stroke development in patients with dementia, particularly AD-related dementia. The pathophysiological progression of stroke in AD cases and the genetic makeup possibly affecting the interrelation between these disorders were analyzed in detail using currently available data and studies. Therapeutic and management modalities already in use for AD were put together, and the possibility of early intervention in such patients benefitting cerebrovascular pathologies, particularly stroke-related, was explored. Prognostic differences between patients of stroke with and without AD were also reviewed, and how appropriate management can reduce the burden on health care settings when both present simultaneously was emphasized.
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Colorectal carcinoma is the third most malignant and second leading cause of death from cancer. The cruelty of this entity is that it takes decades to be symptomatic and is known to be detected late in its timeline by a screening technique. The fatality of this carcinoma only means heightened importance of screening guidelines to be laid down and strict follow-ups by the healthcare providers. A novel method, a potential competitor that could now replace the present screening techniques for colorectal carcinoma, is computed tomographic colonography (CTC) or virtual colonoscopy. Though it first came into existence in 1994, this method is yet to be deeply studied and scrutinized for it to be the next benchmark modality. This review has mainly focused on the various features of CTC. It is contrasted against the gold standard colonoscopy for its superiority, efficacy, cost-effectiveness, patient logistics, and role in detecting extra-colonic lesions. The main focus would be laid on CTC being a screening modality. The review also emphasized why there is a need for the current healthcare providers to incorporate this modality into their practice widely. Although much has been said about CTC and its various aspects of cost-effectiveness, about it being replaced or supplemented for cancer screening, a collaborative effort has to be made by both the fields of radiology and gastroenterology to investigate the outcomes of this not so new technique in daily practice and to avoid misinterpretation of the results due to lack of skill and proficiency.
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Nanoparticles-based multivalent antigen display has the capability of mimicking natural virus infection characteristics, making it useful for eliciting potent long-lasting immune response. Several vaccines are developed against global pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However these subunit vaccines use mammalian expression system, hence mass production with rapid pace is a bigger challenge. In contrast E. coli based subunit vaccine production circumvents these limitations. The objective of the present investigation was to develop nanoparticle vaccine with multivalent display of receptor binding domain (RBD) of SARS-CoV-2 expressed in E. coli. Results showed that RBD entrapped PLA (Poly lactic acid) nanoparticle in combination with aluminum hydroxide elicited 9-fold higher immune responses as compared to RBD adsorbed aluminum hydroxide, a common adjuvant used for human immunization. It was interesting to note that RBD entrapped PLA nanoparticle with aluminum hydroxide not only generated robust and long-lasting antibody response but also provided Th1 and Th2 balanced immune response. Moreover, challenge with 1 µg of RBD alone was able to generate secondary antibody response, suggesting that immunization with RBD-PLA nanoparticles has the ability to elicit memory antibody against RBD. Plaque assay revealed that the antibody generated using the polymeric formulation was able to neutralize SARS-CoV-2. The RBD entrapped PLA nanoparticles blended with aluminum hydroxide thus has potential to develop asa subunit vaccine against COVID-19.
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COVID-19 , Nanopartículas , Hidróxido de Aluminio , Animales , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Formación de Anticuerpos , Vacunas contra la COVID-19 , Escherichia coli , Humanos , Mamíferos , Nanopartículas/química , Poliésteres , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/química , Vacunas de SubunidadRESUMEN
Depression is a psychiatric disorder characterized by various symptoms that can impact one's quality of life. Vitamin D, a fat-soluble vitamin, is well-known for its role in bone health, and research on its effects on mental health has only recently emerged. Vitamin D deficiency is widespread worldwide, and it has been linked to an increased risk of depression. In this article, we have discussed different hypotheses that explain the role of vitamin D in gene expression and its effects on neurotransmitters and different brain functions. We have reviewed literature that shows us that Vitamin D deficiency is a risk factor for depression and explored studies that show us the effects of using or supplementing Vitamin D in preventing depression among various populations.