Global and regional burden of attributable and associated bacterial antimicrobial resistance avertable by vaccination: modelling study

Introduction Antimicrobial resistance (AMR) is a global health threat with 1.27 million and 4.95 million deaths attributable to and associated with bacterial AMR, respectively, in 2019. Our aim is to estimate the vaccine avertable bacterial AMR burden based on existing and future vaccines at the regional and global levels by pathogen and infectious syndromes. Methods We developed a static proportional impact model to estimate the vaccination impact on 15 bacterial pathogens in terms of reduction in age-specific AMR burden estimates for 2019 from the Global Research on Antimicrobial Resistance project in direct proportion to efficacy, coverage, target population for protection, and duration of protection of existing and future vaccines. Results The AMR burden avertable by vaccination in 2019 was highest for the WHO Africa and South-East Asia regions, for lower respiratory infections, tuberculosis, and bloodstream infections by infectious syndromes, and forMycobacterium tuberculosisandStreptococcus pneumoniaeby pathogen. In the baseline scenario for vaccination of primary age groups against 15 pathogens, we estimated vaccine-avertable AMR burden of 0.51 (95% UI 0.49–0.54) million deaths and 28 (27–29) million disability-adjusted life-years (DALYs) associated with bacterial AMR, and 0.15 (0.14–0.17) million deaths and 7.6 (7.1–8.0) million DALYs attributable to AMR globally in 2019. In the high-potential scenario for vaccination of additional age groups against seven pathogens, we estimated vaccine-avertable AMR burden of an additional 1.2 (1.18–1.23) million deaths and 37 (36–39) million DALYs associated with AMR, and 0.33 (0.32–0.34) million deaths and 10 (9.8–11) million DALYs attributable to AMR globally in 2019. Conclusion Increased coverage of existing vaccines and development of new vaccines are effective means to reduce AMR, and this evidence should inform the full value of vaccine assessments

Associations of water, sanitation, and hygiene with typhoid fever in case–control studies: a systematic review and meta-analysis

This work was supported, in whole or in part, by Gavi, the Vaccine Alliance, Bowdoin College, and the Bill & Melinda Gates Foundation, via the Vaccine Impact Modelling Consortium (Grant Number OPP1157270 / INV-009125). The funders were not involved in the study design, data analysis, data interpretation, and writing of the manuscript. The authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy, or views of their affiliated organisationsBackground Water, sanitation, and hygiene (WASH) play a pivotal role in controlling typhoid fever, as it is primarily transmitted through oral-fecal pathways. Given our constrained resources, staying current with the most recent research is crucial. This ensures we remain informed about practical insights regarding effective typhoid fever control strategies across various WASH components. We conducted a systematic review and meta-analysis of case-control studies to estimate the associations of water, sanitation, and hygiene exposures with typhoid fever. Methods We updated the previous review conducted by Brockett et al. We included new findings published between June 2018 and October 2022 in Web of Science, Embase, and PubMed. We used the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool for risk of bias (ROB) assessment. We classified WASH exposures according to the classification provided by the WHO/UNICEF Joint Monitoring Programme for Water Supply, Sanitation, and Hygiene (JMP) update in 2015. We conducted the meta-analyses by only including studies that did not have a critical ROB in both Bayesian and frequentist random-effects models. Results We identified 8 new studies and analyzed 27 studies in total. Our analyses showed that while the general insights on the protective (or harmful) impact of improved (or unimproved) WASH remain the same, the pooled estimates of OR differed. Pooled estimates of limited hygiene (OR = 2.26, 95% CrI: 1.38 to 3.64), untreated water (OR = 1.96, 95% CrI: 1.28 to 3.27) and surface water (OR = 2.14, 95% CrI: 1.03 to 4.06) showed 3% increase, 18% decrease, and 16% increase, respectively, from the existing estimates. On the other hand, improved WASH reduced the odds of typhoid fever with pooled estimates for improved water source (OR = 0.54, 95% CrI: 0.31 to 1.08), basic hygiene (OR = 0.6, 95% CrI: 0.38 to 0.97) and treated water (OR = 0.54, 95% CrI: 0.36 to 0.8) showing 26% decrease, 15% increase, and 8% decrease, respectively, from the existing estimates. Conclusions The updated pooled estimates of ORs for the association of WASH with typhoid fever showed clear changes from the existing estimates. Our study affirms that relatively low-cost WASH strategies such as basic hygiene or water treatment can be an effective tool to provide protection against typhoid fever in addition to other resource-intensive ways to improve WASH

Associations of water, sanitation, and hygiene with typhoid fever in case–control studies: a systematic review and meta-analysis

Background: Water, sanitation, and hygiene (WASH) play a pivotal role in controlling typhoid fever, as it is primarily transmitted through oral-fecal pathways. Given our constrained resources, staying current with the most recent research is crucial. This ensures we remain informed about practical insights regarding effective typhoid fever control strategies across various WASH components. We conducted a systematic review and meta-analysis of case-control studies to estimate the associations of water, sanitation, and hygiene exposures with typhoid fever. Methods: We updated the previous review conducted by Brockett et al. We included new findings published between June 2018 and October 2022 in Web of Science, Embase, and PubMed. We used the Risk of Bias in Non-Randomized Studies of Interventions (ROBINS-I) tool for risk of bias (ROB) assessment. We classified WASH exposures according to the classification provided by the WHO/UNICEF Joint Monitoring Programme for Water Supply, Sanitation, and Hygiene (JMP) update in 2015. We conducted the meta-analyses by only including studies that did not have a critical ROB in both Bayesian and frequentist random-effects models. Results: We identified 8 new studies and analyzed 27 studies in total. Our analyses showed that while the general insights on the protective (or harmful) impact of improved (or unimproved) WASH remain the same, the pooled estimates of OR differed. Pooled estimates of limited hygiene (OR = 2.26, 95% CrI: 1.38 to 3.64), untreated water (OR = 1.96, 95% CrI: 1.28 to 3.27) and surface water (OR = 2.14, 95% CrI: 1.03 to 4.06) showed 3% increase, 18% decrease, and 16% increase, respectively, from the existing estimates. On the other hand, improved WASH reduced the odds of typhoid fever with pooled estimates for improved water source (OR = 0.54, 95% CrI: 0.31 to 1.08), basic hygiene (OR = 0.6, 95% CrI: 0.38 to 0.97) and treated water (OR = 0.54, 95% CrI: 0.36 to 0.8) showing 26% decrease, 15% increase, and 8% decrease, respectively, from the existing estimates. Conclusions: The updated pooled estimates of ORs for the association of WASH with typhoid fever showed clear changes from the existing estimates. Our study affirms that relatively low-cost WASH strategies such as basic hygiene or water treatment can be an effective tool to provide protection against typhoid fever in addition to other resource-intensive ways to improve WASH. Trial registration PROSPERO 2021 CRD42021271881

Estimating the health effects of COVID-19-related immunisation disruptions in 112 countries during 2020-30: a modelling study.

BACKGROUND: There have been declines in global immunisation coverage due to the COVID-19 pandemic. Recovery has begun but is geographically variable. This disruption has led to under-immunised cohorts and interrupted progress in reducing vaccine-preventable disease burden. There have, so far, been few studies of the effects of coverage disruption on vaccine effects. We aimed to quantify the effects of vaccine-coverage disruption on routine and campaign immunisation services, identify cohorts and regions that could particularly benefit from catch-up activities, and establish if losses in effect could be recovered. METHODS: For this modelling study, we used modelling groups from the Vaccine Impact Modelling Consortium from 112 low-income and middle-income countries to estimate vaccine effect for 14 pathogens. One set of modelling estimates used vaccine-coverage data from 1937 to 2021 for a subset of vaccine-preventable, outbreak-prone or priority diseases (ie, measles, rubella, hepatitis B, human papillomavirus [HPV], meningitis A, and yellow fever) to examine mitigation measures, hereafter referred to as recovery runs. The second set of estimates were conducted with vaccine-coverage data from 1937 to 2020, used to calculate effect ratios (ie, the burden averted per dose) for all 14 included vaccines and diseases, hereafter referred to as full runs. Both runs were modelled from Jan 1, 2000, to Dec 31, 2100. Countries were included if they were in the Gavi, the Vaccine Alliance portfolio; had notable burden; or had notable strategic vaccination activities. These countries represented the majority of global vaccine-preventable disease burden. Vaccine coverage was informed by historical estimates from WHO-UNICEF Estimates of National Immunization Coverage and the immunisation repository of WHO for data up to and including 2021. From 2022 onwards, we estimated coverage on the basis of guidance about campaign frequency, non-linear assumptions about the recovery of routine immunisation to pre-disruption magnitude, and 2030 endpoints informed by the WHO Immunization Agenda 2030 aims and expert consultation. We examined three main scenarios: no disruption, baseline recovery, and baseline recovery and catch-up. FINDINGS: We estimated that disruption to measles, rubella, HPV, hepatitis B, meningitis A, and yellow fever vaccination could lead to 49 119 additional deaths (95% credible interval [CrI] 17 248-134 941) during calendar years 2020-30, largely due to measles. For years of vaccination 2020-30 for all 14 pathogens, disruption could lead to a 2·66% (95% CrI 2·52-2·81) reduction in long-term effect from 37 378 194 deaths averted (34 450 249-40 241 202) to 36 410 559 deaths averted (33 515 397-39 241 799). We estimated that catch-up activities could avert 78·9% (40·4-151·4) of excess deaths between calendar years 2023 and 2030 (ie, 18 900 [7037-60 223] of 25 356 [9859-75 073]). INTERPRETATION: Our results highlight the importance of the timing of catch-up activities, considering estimated burden to improve vaccine coverage in affected cohorts. We estimated that mitigation measures for measles and yellow fever were particularly effective at reducing excess burden in the short term. Additionally, the high long-term effect of HPV vaccine as an important cervical-cancer prevention tool warrants continued immunisation efforts after disruption. FUNDING: The Vaccine Impact Modelling Consortium, funded by Gavi, the Vaccine Alliance and the Bill & Melinda Gates Foundation. TRANSLATIONS: For the Arabic, Chinese, French, Portguese and Spanish translations of the abstract see Supplementary Materials section

vaccine-impact/vaccine_amr

Data and code for: "Global and regional burden of attributable and associated bacterial antimicrobial resistance avertable by vaccination: modelling study"

Smoking prevalence among Asian Americans: Associations with education, acculturation, and gender

There is evidence that smoking prevalence rates are related to acculturation, education, and gender among Asian Americans. However, no studies have examined how smoking rates among Asian Americans vary based on acculturation, education, and gender together. This study used National Health Interview Survey (NHIS) data (2010-2018) to examine cigarette smoking prevalence among Asian American men and women aged 18 and older (N = 14,680). Multivariate logistic regression models were used to estimate associations between educa-tional attainment (i.e., college graduate or higher vs some college or lower), years spent in the United States (U. S.) as a proxy for acculturation (i.e., less than 10 years (less acculturated) vs 10 years or more (more accul-turated) vs U.S.-born), and cigarette smoking prevalence across gender controlling for age, marital status, poverty (at/above vs below poverty threshold), country of origin (Chinese vs Filipino vs Asian Indian vs Other Asian), and the survey year. Current smoking prevalence was 9.0 % among all Asian Americans -5.0 % among women and 13.5 % among men. Among respective gender-specific subgroups, U.S.-born Asian women without a college degree and more acculturated Asian immigrant men without a college degree had the highest odds of smoking (OR: 4.096 [95 % CI: 2.638, 6.360] and 1.462 [95 % CI: 1.197, 1.774], respectively). Findings indicated that less educated U.S.-born Asian women and less educated Asian immigrant men are at greatest risk for smoking. Smoking prevalence among Asian Americans is highly related to acculturation, education, and gender. Findings may inform development of policies and programs that are targeted toward smoking cessation among Asian Americans.Y

Hydroxy Pentacyclic Triterpene Acid, Kaempferol, Inhibits the Human 5-Hydroxytryptamine Type 3A Receptor Activity

Monoamine serotonin is a major neurotransmitter that acts on a wide range of central nervous system and peripheral nervous system functions and is known to have a role in various processes. Recently, it has been found that 5-HT is involved in cognitive and memory functions through interaction with cholinergic pathways. The natural flavonoid kaempferol (KAE) extracted from Cudrania tricuspidata is a secondary metabolite of the plant. Recently studies have confirmed that KAE possesses a neuroprotective effect because of its strong antioxidant activity. It has been confirmed that KAE is involved in the serotonergic pathway through an in vivo test. However, these results need to be confirmed at the molecular level, because the exact mechanism that is involved in such effects of KAE has not yet been elucidated. Therefore, the objective of this study is to confirm the interaction of KAE with 5-HT3A through electrophysiological studies at the molecular level using KAE extracted from Cudrania tricuspidata. This study confirmed the interaction between 5-HT3A and KAE at the molecular level. KAE inhibited 5-HT3A receptors in a concentration-dependent and voltage-independent manner. Site-directed mutagenesis and molecular-docking studies confirmed that the binding sites D177 and F199 are the major binding sites of human 5-HT3A receptors of KAE

Acquired Resistance Mechanism of EGFR Kinase Domain Duplication to EGFR TKIs in Non–Small Cell Lung Cancer

Copyright © 2022 by the Korean Cancer Association.Purpose Epidermal growth factor receptor kinase domain duplication (EGFR-KDD) is a rare and poorly understood oncogenic mutation in non–small cell lung cancer (NSCLC). We aimed to investigate the acquired resistance mechanism of EGFR-KDD against EGFR-TKIs. Materials and Methods We identified EGFR-KDD in tumor tissue obtained from a patient with stage IV lung adenocarcinoma and established the patient-derived cell line SNU-4784. We also established several EGFR-KDD Ba/F3 cell lines: EGFR-KDD wild type (EGFR-KDDWT), EGFR-KDD domain 1 T790M (EGFR-KDDD1T), EGFR-KDD domain 2 T790M (EGFR-KDDD2T), and EGFR-KDD both domain T790M (EGFR-KDDBDT). We treated the cells with EGFR tyrosine kinase inhibitors (TKIs) and performed cell viability assays, immunoblot assays, and ENU (N-ethyl-N-nitrosourea) mutagenesis screening. Results In cell viability assays, SNU-4784 cells and EGFR-KDDWT Ba/F3 cells were sensitive to 2nd generation and 3rd generation EGFR TKIs. In contrast, the T790M-positive EGFR-KDD Ba/F3 cell lines (EGFR-KDDT790M) were only sensitive to 3rd generation EGFR TKIs. In ENU mutagenesis screening, we identified the C797S mutation in kinase domain 2 of EGFR-KDDBDT Ba/F3 cells. Based on this finding, we established an EGFR-KDD domain 1 T790M/domain 2 cis-T790M+C797S (EGFR-KDDT/T+C) Ba/F3 model, which was resistant to EGFR TKIs and anti-EGFR monoclonal antibody combined with EGFR TKIs. Conclusion Our study reveals that the T790M mutation in EGFR-KDD confers resistance to 1st and 2nd generation EGFR TKIs, but is sensitive to 3rd generation EGFR TKIs. In addition, we identified that the C797S mutation in kinase domain 2 of EGFR-KDDT790M mediates a resistance mechanism against 3rd generation EGFR TKIs.N

Differential Regulation of Human Serotonin Receptor Type 3A by Chanoclavine and Ergonovine

Irritable bowel syndrome (IBS) is a chronic disease that causes abdominal pain and an imbalance of defecation patterns due to gastrointestinal dysfunction. The cause of IBS remains unclear, but intestinal-brain axis problems and neurotransmitters have been suggested as factors. In this study, chanoclavine, which has a ring structure similar to 5-hydroxytryptamine (5-HT), showed an interaction with the 5-HT3A receptor to regulate IBS. Although its derivatives are known to be involved in neurotransmitter receptors, the molecular physiological mechanism of the interaction between chanoclavine and the 5-HT3A receptor is unknown. Electrophysiological experiments were conducted using a two-electrode voltage-clamp analysis to observe the inhibitory effects of chanoclavine on Xenopus oocytes in which the h5-HT3A receptor was expressed. The co-application of chanoclavine and 5-HT resulted in concentration-dependent, reversible, voltage-independent, and competitive inhibition. The 5-HT3A response induced by 5-HT was blocked by chanoclavine with half-maximal inhibitory response concentration (IC50) values of 107.2 µM. Docking studies suggested that chanoclavine was positioned close F130 and N138 in the 5-HT3A receptor-binding site. The double mutation of F130A and N138A significantly attenuated the interaction of chanoclavine compared to a single mutation or the wild type. These data suggest that F130 and N138 are important sites for ligand binding and activity. Chanoclavine and ergonovine have different effects. Asparagine, the 130th amino acid sequence of the 5-HT3A receptor, and phenylalanine, the 138th, are important in the role of binding chanoclavine, but ergonovine has no interaction with any amino acid sequence of the 5-HT3A receptor. The results of the electrophysiological studies and of in silico simulation showed that chanoclavine has the potential to inhibit the hypergastric stimulation of the gut by inhibiting the stimulation of signal transduction through 5-HT3A receptor stimulation. These findings suggest chanoclavine as a potential antiemetic agent for excessive gut stimulation and offer insight into the mechanisms of 5-HT3A receptor inhibition

Chiral Supramolecular Gels with Lanthanide Ions: Correlation between Luminescence and Helical Pitch

We report the correlation between the fluorescence intensity and the helical pitch of supramolecular hydrogels with Tb­(III) and Eu­(III) as well as their inkjet printing patterning as an application. The luminescent gels, which exhibited three different emissions of red, green, and blue, could be prepared without and with Eu­(III) and Tb­(III). The luminescence intensity of supramolecular gels (gel-Tb and gel-Eu) composed of Tb­(III) and Eu­(III) was ca. 3-fold larger than that of the sol (<b>1</b>+Tb­(III) or <b>1</b>+Eu­(III)), which was attributed to large tilting angles between molecules. By AFM observations, these gels showed well-defined right-handed helical nanofibers formed by coordination bonds in which the helical pitch lengths were strongly dependent on the concentrations of lanthanide ions. In particular, the large luminescence intensity of gel-Tb exhibited a smaller helical pitch length than that of gel-<b>1</b> due to relatively weak π–π stacking with large tilting angles between molecules. The luminescence intensities were enhanced linearly with increasing concentrations of lanthanide ions. This is the first example of the correlation between the helical pitch length and the luminescence intensity of supramolecular materials. The coordination bonding in supramolecular hydrogels had a strong influence on rheological properties. We also developed a water-compatible inkjet printing system to generate luminescent supramolecular gels on A4-sized paper. The images of a logo and the text were composed of three different emissions and were well-printed on A4 sized paper coated with gel-<b>1</b>